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.
About 20 years ago, urolithins are discovered as bioavailable metabolites produced by the human gut microbiota from ellagitannins and ellagic acid. Pioneering investigations suggested pleiotropic effects for urolithins that growing evidence confirms, especially for urolithin A. Here, we update the knowledge on urolithins metabolism, bioactivity, and associated gut microbiota, emphasizing the literature published in the last 5 years.
Flavanones, flavonoids abundant in Citrus, have been shown to interfere with quorum sensing (QS) and affect related physiological processes. We have investigated the QS-inhibitory effects of an ...orange extract enriched in O-glycosylated flavanones (mainly naringin, neohesperidin, and hesperidin). The QS-inhibitory capacity of this extract and its main flavanone components was first screened using the bacteriological monitoring system Chromobacterium violaceum. We next examined the ability of the orange extract and of some of the flavanones to (i) reduce the levels of the QS mediators produced by Y. enterocolitica using HPLC-MS/MS, (ii) inhibit biofilm formation, and (iii) inhibit swimming and swarming motility. Additionally, we evaluated changes in the expression of specific genes involved in the synthesis of the lactones (yenI, yenR) and in the flagellar regulon (flhDC, fleB, fliA) by RT-PCR. The results showed that the orange extract and its main flavanone components inhibited QS in C. violaceum, diminished the levels of lactones secreted by Y. enterocolitica to the media, and decreased QS-associated biofilm maturation without affecting bacterial growth. Among the tested compounds, naringin was found to inhibit swimming motility. Exposure to the orange extract and (or) to naringin was also found to be associated with induction of the transcription levels of yenR, flhDC, and fliA. This work shows the in vitro QS-inhibitory effects of an orange extract enriched in flavanones against a human enteropathogen at doses that can be achieved through the diet and suggests that consumption of these natural extracts may have a beneficial antipathogenic effect.
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.
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 (PGE
), 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.
Buckwheat (BW) is a gluten-free pseudocereal that belongs to the Polygonaceae family. BW grain is a highly nutritional food component that has been shown to provide a wide range of beneficial ...effects. Health benefits attributed to BW include plasma cholesterol level reduction, neuroprotection, anticancer, anti-inflammatory, antidiabetic effects, and improvement of hypertension conditions. In addition, BW has been reported to possess prebiotic and antioxidant activities. In vitro and animal studies suggest that BW’s bioactive compounds, such as d-chiro-inositol (DCI), BW proteins (BWP), and BW flavonoids (mainly rutin and quercetin) may be partially responsible for the observed effects. The purpose of this paper is to review the recent research regarding the health benefits of BW, in vitro and in vivo, focusing on the specific role of its bioactive compounds and on the mechanisms by which these effects are exerted.
Alzheimer’s disease (AD) is a prototypical inflammation-associated loss of cognitive function, with approximately 90% of the AD burden associated with invading myeloid cells controlling the function ...of the resident microglia. This indicates that the immune microenvironment has a pivotal role in the pathogenesis of the disease. Multiple peripheral stimuli, conditioned by complex and varied interactions between signals that stem at the intestinal level and neuroimmune processes, are involved in the progression and severity of AD. Conceivably, the targeting of critical innate immune signals and cells is achievable, influencing immune and metabolic health within the gut–brain axis. Considerable progress has been made, modulating many different metabolic and immune alterations that can drive AD development. However, non-pharmacological strategies targeting immunometabolic processes affecting neuroinflammation in AD treatment remain general and, at this point, are applied to all patients regardless of disease features. Despite these possibilities, improved knowledge of the relative contribution of the different innate immune cells and molecules comprising the chronically inflamed brain network to AD pathogenesis, and elucidation of the network hierarchy, are needed for planning potent preventive and/or therapeutic interventions. Moreover, an integrative perspective addressing transdisciplinary fields can significantly contribute to molecular pathological epidemiology, improving the health and quality of life of AD patients. This review is intended to gather modifiable immunometabolic processes based on their importance in the prevention and management of AD.
Pomegranate ellagitannins (ETs) are transformed in the gut to ellagic acid (EA) and its microbiota metabolites, urolithin A (Uro-A) and urolithin B (Uro-B). These compounds exert anti-inflammatory ...effects in vitro and in vivo. The aim of this study was to investigate the effects of Uro-A, Uro-B, and EA on colon fibroblasts, cells that play a key role in intestinal inflammation. CCD18-Co colon fibroblasts were exposed to a mixture of Uro-A, Uro-B, and EA, at concentrations comparable to those found in the colon (40 μM Uro-A, 5 μM Uro-B, 1 μM EA), both in the presence or in the absence of IL-1β (1 ng/mL) or TNF-α (50 ng/mL), and the effects on fibroblast migration and monocyte adhesion were determined. The levels of several growth factors and adhesion cytokines were also measured. The mixture of metabolites significantly inhibited colon fibroblast migration (∼70%) and monocyte adhesion to fibroblasts (∼50%). These effects were concomitant with a significant down-regulation of the levels of PGE2, PAI-1, and IL-8, as well as other key regulators of cell migration and adhesion. Of the three metabolites tested, Uro-A exhibited the most significant anti-inflammatory effects. The results show that a combination of the ET metabolites found in colon, urolithins and EA, at concentrations achievable in the intestine after the consumption of pomegranate, was able to moderately improve the inflammatory response of colon fibroblasts and suggest that consumption of ET-containing foods has potential beneficial effects on gut inflammatory diseases.
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,
.). 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 (
, 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.
Scope
Recent evidence demonstrates that resveratrol (RSV) metabolites, but not free RSV, reach malignant tumors (MT) in breast cancer (BC) patients. Since these metabolites, as detected in MT, do not ...exert short‐term antiproliferative or estrogenic/antiestrogenic activities, long‐term tumor‐senescent chemoprevention has been hypothesized. Consequently, here, for the first time, whether physiologically relevant RSV metabolites can induce senescence in BC cells is investigated.
Methods and Results
Human BC MCF‐7 (wild‐type p53) and MDA‐MB‐231 (mutant p53), and non‐tumorigenic MCF‐10A cells are treated with free RSV and physiological‐derived metabolites (RSV 3‐O‐glucuronide, RSV 3‐O‐sulfate, RSV 4′‐O‐sulfate, dihydroresveratrol (DH‐RSV), and DH‐RSV 3‐Oglucuronide). Cellular senescence is measured by SA‐β‐gal activity and senescence‐associated markers (p53, p21Cip1/Waf1, p16INK4a, and phosphorylation status of retinoblastoma (pRb/tRb)). Although no effect is observed in MDA‐MB‐231 and normal cells, RSV metabolites induce cellular senescence in MCF‐7 cells by reducing their clonogenic capacity and arresting cell cycle at G2M/S phase, but do not induce apoptosis. Senescence is induced through the p53/p21Cip1/Waf1 and p16INK4a/Rb pathways, depending on the RSV metabolite, and requires ABC transporters, but not estrogen receptors.
Conclusions
These data suggest that RSV metabolites, as found in MT from BC patients, are not de‐conjugated to release free RSV, but enter the cells and may exert long‐term tumor‐senescent chemoprevention.
Physiologically relevant resveratrol (RSV) metabolites, as found in malignant tissues from breast cancer (BC) patients, induce cellular senescence in BC cells but not in non‐tumorigenic cells. Senescence is induced through the p53/p21 and p16/Rb pathways, depending on the RSV‐metabolite, and requires ABC transporters but not estrogen receptors. This mechanism might be involved in BC chemoprevention upon consumption of RSV‐containing foods.
.
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–1 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–1 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.
A total of 47 curcuminoid, isoflavone, resveratrol, and lignan‐derived metabolites, mostly conjugated, were detected in malignant mammary tissues of breast cancer patients. However, free curcumin, but not its glucuronide, was detected at micromolar concentration, likely due to a glucuronidation‐saturation process. Breast tissue‐occurring metabolites, mainly, curcuminoids, induced cell cycle arrest, senescence, and apoptosis via p53/p21, while isoflavone metabolites exerted estrogenic activity.
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