Neuroprotective Effects of Bioavailable Polyphenol-Derived Metabolites against Oxidative Stress-Induced Cytotoxicity in Human Neuroblastoma SH-SY5Y Cells

Oxidative stress is involved in cell death in neurodegenerative diseases. Dietary polyphenols can exert health benefits, but their direct effects on neuronal cells are debatable because most phenolics are metabolized and do not reach the brain as they occur in the dietary sources. Herein, we evaluate the effects of a panel of bioavailable polyphenols and derived metabolites at physiologically relevant conditions against H2O2-induced apoptosis in human neuroblastoma SH-SY5Y cells. Among the 19 metabolites tested, 3,4-dihydroxyphenylpropionic acid, 3,4-dihydroxyphenylacetic acid, gallic acid, ellagic acid, and urolithins prevented neuronal apoptosis via attenuation of ROS levels, increased REDOX activity, and decreased oxidative stress-induced apoptosis by preventing the caspase-3 activation via the mitochondrial apoptotic pathway in SH-SY5Y cells. This suggests that dietary sources containing the polyphenol precursors of these molecules such as cocoa, berries, walnuts, and tea could be potential functional foods to reduce oxidative stress associated with the onset and progress of neurodegenerative diseases.This work was funded by Projects CICYT AGL2011-22447, AGL2015-64124-R (MINECO, Spain), 201370E068 (CSIC, Spain), and BACCHUS (FP7-KBBE-2012-6-single stage, European Commission Grant Agreement 312090). A.G.-S. and M.A.N.-S. are holders of a “Juan de la Cierva” contract and an FPI grant, respectively, from MINECO.Peer reviewe

Can exosomes transfer the preconditioning effects triggered by (poly)phenol compounds between cells?

Funding Information: This work has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme under grant agreement No 804229. This work was also supported by “iNOVA4Health – UIDB/04462/2020 and UIDP/04462/2020, and by the Associated Laboratory LS4FUTURE (LA/P/0087/2020), two programs financially supported by Fundação para a Ciência e Tecnologia/Ministério da Ciência, Tecnologia e Ensino Superior. This work has also been funded by the project PID2019-103914RB-I00 from the Ministry of Science and Innovation (MICINN, Spain). We also acknowledge EMBO Installation Grant 3921, the grant 2017NovPCC1058 from Breast Cancer Now's Catalyst Programme, which is supported by funding from Pfizer, the grant 765492 from H2020-MSCA-ITN-2017, the Champalimaud Foundation and the grant LCF/PR/HR19/52160014 from “La Caixa” Foundation. Publisher Copyright: © 2023 The Royal Society of Chemistry.Effective strategies in prolonging life- and health span are increasingly recognized as acting as mild stressors. Micronutrients and other dietary compounds such as (poly)phenols may act as moderate stressors and confer protective effects via a preconditioning phenomenon. (Poly)phenols and their metabolites may not need to reach their target cells to produce biologically significant responses, so that cells exposed to it at entry points may communicate signals to other cells. One of such “communication” mechanisms could occur through extracellular vesicles, including exosomes. In vitro loading of exosomes with (poly)phenols has been used to achieve targeted exosome homing. However, it is unknown if similar shuttling phenomena occur in vivo upon (poly)phenols consumption. Alternatively, exposure to (poly)phenols might trigger responses in exposed organs, which can subsequently signal to cells distant from exposure sites via exosomes. The currently available studies favor indirect effects of (poly)phenols, tempting to suggest a “billiard-like” or “domino-like” propagating effect mediated by quantitative and qualitative changes in exosomes triggered by (poly)phenols. In this review, we discuss the limited current data available on how (poly)phenols exposure can potentially modify exosomes activity, highlighting major questions regarding how (epi)genetic, physiological, and gut microbiota factors can modulate and be modulated by the putative exosome-(poly)phenolic compound interplay that still remains to be fully understood.publishersversionpublishe

A systematic review and meta-analysis of the effects of flavanol-containing tea, cocoa and apple products on body composition and blood lipids: exploring the factors responsible for variability in their efficacy

Several randomized controlled trials (RCTs) and meta-analyses support the benefits of flavanols on cardiometabolic health, but the factors affecting variability in the responses to these compounds have not been properly assessed. The objectives of this meta-analysis were to systematically collect the RCTs-based-evidence of the effects of flavanol-containing tea, cocoa and apple products on selected biomarkers of cardiometabolic risk and to explore the influence of various factors on the variability in the responses to the consumption of these products. A total of 120 RCTs were selected. Despite a high heterogeneity, the intake of the flavanol-containing products was associated using a random model with changes (reported as standardized difference in means (SDM)) in body mass index (−0.15, p < 0.001), waist circumference (−0.29, p < 0.001), total-cholesterol (−0.21, p < 0.001), LDL-cholesterol (−0.23, p < 0.001), and triacylglycerides (−0.11, p = 0.027), and with an increase of HDL-cholesterol (0.15, p = 0.005). Through subgroup analyses, we showed the influence of baseline-BMI, sex, source/form of administration, medication and country of investigation on some of the outcome measures and suggest that flavanols may be more effective in specific subgroups such as those with a BMI ≥ 25.0 kg/m2, non-medicated individuals or by specifically using tea products. This meta-analysis provides the first robust evidence of the effects induced by the consumption of flavanol-containing tea, cocoa and apple products on weight and lipid biomarkers and shows the influence of various factors that can affect their bioefficacy in humans. Of note, some of these effects are quantitatively comparable to those produced by drugs, life-style changes or other natural products. Further, RCTs in well-characterized populations are required to fully comprehend the factors affecting inter-individual responses to flavanol and thereby improve flavanols efficacy in the prevention of cardiometabolic disorders

Metabolite production and/or gut microbiota-associated metabotypes?

Funding Information: This research was supported by the Project PID2019-103914RB-I00 from the Ministry of Science and Innovation (MICINN, Spain) and by Fundación Séneca de la Región de Murcia (Spain), grant number 20880/PI/18. 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. A.C.M. and C.E.I.-A. are the holders of predoctoral grants from MINECO (grant number BES-2016-078098) and MICINN (grant number FPU18/03961) (Spain), respectively. Publisher Copyright: © 2021 The Royal Society of Chemistry.Despite the high human interindividual variability in response to (poly)phenol consumption, the cause-and-effect relationship between some dietary (poly)phenols (flavanols and olive oil phenolics) and health effects (endothelial function and prevention of LDL oxidation, respectively) has been well established. Most of the variables affecting this interindividual variability have been identified (food matrix, gut microbiota, single-nucleotide-polymorphisms, etc.). However, the final drivers for the health effects of (poly)phenol consumption have not been fully identified. At least partially, these drivers could be (i) the (poly)phenols ingested that exert their effect in the gastrointestinal tract, (ii) the bioavailable metabolites that exert their effects systemically and/or (iii) the gut microbial ecology associated with (poly)phenol metabolism (i.e., gut microbiota-associated metabotypes). However, statistical associations between health effects and the occurrence of circulating and/or excreted metabolites, as well as cross-sectional studies that correlate gut microbial ecologies and health, do not prove a causal role unequivocally. We provide a critical overview and perspective on the possible main drivers of the effects of (poly)phenols on human health and suggest possible actions to identify the putative actors responsible for the effects.publishersversionpublishe

Dietary Phenolics against Breast Cancer. A Critical Evidence-Based Review and Future Perspectives

© 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 discussedThis 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 reviewe

The gut microbiota metabolism of pomegranate or walnut ellagitannins yields two urolithin-metabotypes that correlate with cardiometabolic risk biomarkers: Comparison between normoweight, overweight-obesity and metabolic syndrome.

Background & aims: Urolithins are microbial metabolites produced after consumption of ellagitannincontaining foods such as pomegranates and walnuts. Parallel to isoflavone-metabolizing phenotypes, ellagitannin-metabolizing phenotypes (urolithin metabotypes A, B and 0; UM-A, UM-B and UM-0, respectively) can vary among individuals depending on their body mass index (BMI), but correlations between urolithin metabotypes (UMs) and cardiometabolic risk (CMR) factors are unexplored. We investigated the association between UMs and CMR factors in individuals with different BMI and health status. Methods: UM was identified using UPLC-ESI-qToF-MS in individuals consuming pomegranate or nuts. The associations between basal CMR factors and the urine urolithin metabolomic signature were explored in 20 healthy normoweight individuals consuming walnuts (30 g/d), 49 healthy overweightobese individuals ingesting pomegranate extract (450 mg/d) and 25 metabolic syndrome (MetS) patients consuming nuts (15 g-walnuts, 7.5 g-hazelnuts and 7.5 g-almonds/d). Results: Correlations between CMR factors and urolithins were found in overweight-obese individuals. Urolithin-A (mostly present in UM-A) was positively correlated with apolipoprotein A-I (P 0.05) and intermediate-HDL-cholesterol (P 0.05) while urolithin-B and isourolithin-A (characteristic from UM-B) were positively correlated with total-cholesterol, LDL-cholesterol (P 0.001), apolipoprotein B (P 0.01), VLDL-cholesterol, IDL-cholesterol, oxidized-LDL and apolipoprotein B:apolipoprotein A-I ratio (P 0.05). In MetS patients, urolithin-A only correlated inversely with glucose (P 0.05). Statin-treated MetS patients with UM-A showed a lipid profile similar to that of healthy normoweight individuals while a poor response to lipid-lowering therapy was observed in MB patients. Conclusions: UMs are potential CMR biomarkers. Overweight-obese individuals with UM-B are at increased risk of cardiometabolic disease, whereas urolithin-A production could protect against CMR factors. Further research is warranted to explore these associations in larger cohorts and whether the effect of lipidlowering drugs or ellagitannin-consumption on CMR biomarkers depends on individuals' UM

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

Producción CientíficaEllagic 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.Ministerio de Economía, Industria y Competitividad (AGL2013-48943-C2-2-R and IPT-2011-1248-060000)Comunidad de Madrid [Grant P2013/ABI-2728 ALIBIRD-CM

Synthesis, Characterisation, and Preliminary In Vitro Studies of Vanadium(IV) Complexes with a Schiff Base and Thiosemicarbazones as Mixed Ligands

[VO(sal‐L‐tryp)(H2O)] (1, sal‐L‐tryp = N‐salicylidene‐L‐tryptophanate) was used as a precursor to produce the new complexes [VO(sal‐L‐tryp)(MeATSC)]·1.5C2H5OH [2, MeATSC = 9‐Anthraldehyde‐N(4)‐methylthiosemicarbazone], [VO(sal‐L‐tryp)(N‐ethhymethohcarbthio)]·H2O [3, N‐ethhymethohcarbthio = (E)‐N‐ethyl‐2‐(4‐hydroxy‐3‐methoxybenzylidene)hydrazinecarbothioamide] and [VO(sal‐L‐tryp)(acetylethTSC)]·C2H5OH {4, acetylethTSC = (E)‐N‐ethyl‐2‐[1‐(thiazol‐2‐yl)ethylidene]hydrazinecarbothioamide} by reaction with the respective thiosemicarbazone. The chemical and structural properties of these ligands and complexes were characterised by elemental analysis, ESI‐MS, FTIR, UV/Vis, ESR and 1H and 13C NMR spectroscopy and X‐ray crystallography. Dimethyl sulfoxide (DMSO) and [D6]DMSO solutions of 1–4 were oxidised in air to produce vanadium(V) species, which were verified by ESI‐MS and 51V NMR spectroscopy. The anticancer properties of 2–4 were examined with three colon cancer cell lines, HTC‐116, Caco‐2 and HT‐29, and noncancerous colonic myofibroblasts, CCD18‐Co. Compounds 2–3 exhibited less inhibitory effects in the CCD‐18Co cells, which indicates a possible cytotoxic selectivity towards colon cancer cells. In general, compounds that exhibit antiproliferative activity to cancer cells but do not affect noncancerous cells may have a potential in chemotherapy

Meta-Analysis of the Effects of Foods and Derived Products Containing Ellagitannins and Anthocyanins on Cardiometabolic Biomarkers: Analysis of Factors Influencing Variability of the Individual Responses

peer-reviewedUnderstanding interindividual variability in response to dietary polyphenols remains essential to elucidate their effects on cardiometabolic disease development. A meta-analysis of 128 randomized clinical trials was conducted to investigate the effects of berries and red grapes/wine as sources of anthocyanins and of nuts and pomegranate as sources of ellagitannins on a range of cardiometabolic risk biomarkers. The potential influence of various demographic and lifestyle factors on the variability in the response to these products were explored. Both anthocyanin- and ellagitannin-containing products reduced total-cholesterol with nuts and berries yielding more significant effects than pomegranate and grapes. Blood pressure was significantly reduced by the two main sources of anthocyanins, berries and red grapes/wine, whereas waist circumference, LDL-cholesterol, triglycerides, and glucose were most significantly lowered by the ellagitannin-products, particularly nuts. Additionally, we found an indication of a small increase in HDL-cholesterol most significant with nuts and, in flow-mediated dilation by nuts and berries. Most of these effects were detected in obese/overweight people but we found limited or non-evidence in normoweight individuals or of the influence of sex or smoking status. The effects of other factors, i.e., habitual diet, health status or country where the study was conducted, were inconsistent and require further investigation.This article is based upon work from COST Action FA1403—POSITIVe “Interindividual variation in response to consumption of plant food bioactives and determinants involved” supported by COST (European Cooperation in Science and Technology, http://www.cost.eu/). The authors thank the financial support of the COST Action FA1403 “POSITIVe” to conduct a short-term scientific mission to K.C. at CEBAS-CSIC (A.G.-S. and M.T.G.-C.) during which the data analysis was performed

Improving the reporting quality of intervention trials addressing the inter-individual variability in response to the consumption of plant bioactives: quality index and recommendations

PURPOSE: The quality of the study design and data reporting in human trials dealing with the inter-individual variability in response to the consumption of plant bioactives is, in general, low. There is a lack of recommendations supporting the scientific community on this topic. This study aimed at developing a quality index to assist the assessment of the reporting quality of intervention trials addressing the inter-individual variability in response to plant bioactive consumption. Recommendations for better designing and reporting studies were discussed. METHODS: The selection of the parameters used for the development of the quality index was carried out in agreement with the scientific community through a survey. Parameters were defined, grouped into categories, and scored for different quality levels. The applicability of the scoring system was tested in terms of consistency and effort, and its validity was assessed by comparison with a simultaneous evaluation by experts' criteria. RESULTS: The "POSITIVe quality index" included 11 reporting criteria grouped into four categories (Statistics, Reporting, Data presentation, and Individual data availability). It was supported by detailed definitions and guidance for their scoring. The quality index score was tested, and the index demonstrated to be valid, reliable, and responsive. CONCLUSIONS: The evaluation of the reporting quality of studies addressing inter-individual variability in response to plant bioactives highlighted the aspects requiring major improvements. Specific tools and recommendations favoring a complete and transparent reporting on inter-individual variability have been provided to support the scientific community on this field