Scope
Carnosic acid (CA) and derived diterpenes abundant in rosemary extracts (REs) exert anti‐obesity effects. The aim of this study was to investigate the bioavailability of these compounds in a ...rat model of obesity.
Methods and results
A total of 26 compounds were tentatively identified based on accurate mass information and the isotopic pattern provided by TOF‐MS analyzer. The main metabolites detected in the gut content, liver, and plasma were the glucuronide conjugates of CA, carnosol, and rosmanol. Two other metabolites were also identified: CA 12‐methyl ether and 5,6,7,10‐tetrahydro‐7‐hydroxyrosmariquinone. All the metabolites were detected as early as 25 min following oral administration. Most of the compounds remained in the intestine, liver, and (or) plasma at substantial concentrations for several hours supporting their potential health benefits in these tissues. We also corroborated the presence of small quantities of CA and detected trace quantities of the main CA metabolites in the brain. Notably, we did not find significant differences in the metabolic profile between lean and obese rats.
Conclusion
We report for the first time a comprehensive profile of metabolites in various organs following the oral consumption of an RE enriched in CA and contribute to establish the potential bioactive molecules.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Scope
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.
Methods and results
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.
Conclusion
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.
Physiologically relevant (qualitatively and quantitatively) mixtures of ellagitannin metabolites, mimicking human urolithin metabotypes, as well as the individual compounds (Uro‐A ∼ IsoUro‐A ∼ Uro‐C ∼ Uro‐D > Uro‐B ∼ EA) exert cell‐specific anticancer effects (cell proliferation inhibition and cell‐cycle arrest) against colon cancer cells via a common induction of CDKN1A with the involvement of specific microRNAs.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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.
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IJS, KILJ, NUK, PNG, UL, UM, UPUK
Colorectal cancer (CRC) remains a major cause of cancer death worldwide. Over 70% of CRC cases are sporadic and related to lifestyle. Epidemiological studies inversely correlate CRC incidence with ...the intake of fruits and vegetables but not with their phenolic content. Preclinical studies using in vitro (cell lines) and animal models of CRC have reported anticancer effects for dietary phenolics through the regulation of different markers and signaling pathways. Herein, we review and contrast the evidence between preclinical studies and clinical trials (patients with CRC or at risk, familial adenopolyposis or aberrant crypt foci) investigating the protective effects of curcumin, resveratrol, isoflavones, green tea extracts (epigallocatechin gallate), black raspberry powder (anthocyanins and ellagitannins), bilberry extract (anthocyanins), ginger extracts (gingerol derivatives), and pomegranate extracts (ellagitannins and ellagic acid). To date, curcumin is the most promising polyphenol as possible future adjuvant in CRC management. Overall, the clinical evidence of dietary phenolics against CRC is still weak and the amounts needed to exert some effects largely exceed common dietary doses. We discuss here the possible reasons behind the gap between preclinical and clinical research (inconsistence of results, lack of clinical endpoints, etc.), and provide an outlook and a roadmap to approach this topic.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Novel gene expression profiles and cellular functions modulated in Caco‐2 cells in response to the dietary polyphenol, ellagic acid (EA), and its colonic metabolites, urolithin‐A ...(3,8‐dihydroxy‐6H‐dibenzob,d pyran‐6‐one) and urolithin‐B (3‐hydroxy‐6H‐dibenzob,d pyran‐6‐one) have been identified. Exposure of cells to EA and urolithins arrested cell growth at the S‐ and G2/M‐phases. Transcriptional profiling using microarray and functional analysis revealed changes in the expression levels of MAPK signalling genes such as, growth factor receptors (FGFR2, EGFR), oncogenes (K‐Ras, c‐Myc), and tumour suppressors (DUSP6, Fos) and of genes involved in cell cycle (CCNB1, CCNB1IP1). Results suggest that EA and urolithin‐A and ‐B, at concentrations achievable in the lumen from the diet, might contribute to colon cancer prevention by modulating the expression of multiple genes in epithelial cells lining the colon. Some of these genes are involved in key cellular processes associated with cancer development and are currently being investigated as potential chemopreventive targets.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
PURPOSE: Urolithins, gut microbiota metabolites derived from ellagic acid and ellagitannins, reach micromolar concentrations in the colon lumen where can have anti-inflammatory and anticancer ...effects. The antiproliferative activity of urolithins (Uro-A, Uro-B, Uro-C and Uro-D) and their most relevant in vivo glucuronides were evaluated in three human colon cancer cell lines (Caco-2, SW480 and HT-29). METHODS: Cell proliferation was evaluated by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide and Trypan blue exclusion assays. Cell cycle was evaluated by flow cytometry and urolithins metabolism by HPLC–MS/MS. RESULTS: Urolithins inhibited cell proliferation and cell cycle progression in a time- and dose-dependent manner and arrested the cells at S and G2/M phases, depending on the urolithin. Uro-A exerted the highest antiproliferative activity, followed by Uro-C, Uro-D and Uro-B. Unlike Caco-2 and SW480 cells, HT-29 cells partially overcame the effects after 48 h, which was related to the complete glucuronidation of urolithins. Uro-A or Uro-B glucuronides did not affect cell cycle and showed lower antiproliferative activity than their aglycone counterparts. Uro-A or Uro-B plus inhibitors of drug efflux ABC transporters partially prevented the glucuronidation of urolithins in HT-29 cells which became more sensitive. CONCLUSIONS: Uro-A, Uro-B, Uro-C and Uro-D exerted different antiproliferative effects depending on the colon cancer cell line. We also report here, for the first time, the role of ABC transporters and Phase-II metabolism in HT-29 cells as a mechanism of cancer resistance against urolithins due to their conversion to glucuronide conjugates that exerted lower antiproliferative activity.
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DOBA, EMUNI, FIS, FSPLJ, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
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.
Increased understanding of subjective well-being (SWB), as well as factors that influence it, are essential to enhance well-being at the individual and national level. We have applied a hedonic and ...eudaimonic 9-item composed tool (SWB score) to measure SWB across several Mediterranean (MED) and non-Mediterranean (non-MED) countries, and to explore the association between the SWB score and a range of sociodemographic, health and Mediterranean lifestyle factors. A specifically designed web-based questionnaire was distributed to adult participants (N = 2400) from Spain, Italy, Portugal, Bulgaria and Republic of North Macedonia. Results showed that the SWB score was significantly different across the examined countries with the MED participants displaying slightly higher average scores than the non-MED ones (6.3 ± 1.5 vs. 6.1 ± 1.6,
= 0.002). Several sociodemographic, health status and lifestyle factors displayed a significant but limited association with the 9-item SWB score, with a multiple regression model explaining around 17% of the variance. Nevertheless, our results support that a closer adherence to Mediterranean lifestyle habits-the Mediterranean Diet, spending time with friends, family, and in nature, being active, and getting adequate rest at night-has a positive influence on the 9-item SWB score. Further research is needed to advance the understanding of the measuring and differentiating of SWB across different populations and to establish all the factors that influence it.
Understanding 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.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
SCOPE: Carnosic acid (CA) and rosemary extracts (REs) have antiobesity effects but the mechanisms are not understood. We investigated some of the potential mechanisms contributing to the metabolic ...effects of an RE enriched in CA. METHODS AND RESULTS: An RE (∼40% CA) was administered to lean (Le, fa/+) and obese (Ob, fa/fa) female Zucker rats for 64 days. Several adipocytokines, brain‐derived neurotrophic factor, phosphorylated AMP‐activated protein kinase, and hepatic gene expression changes were investigated. The RE significantly decreased circulating tumor necrosis factor alpha (RE/CT = 0.36, p < 0.0003), IL‐1β (0.48, p < 0.032), and leptin (0.48, p < 0.002), and upregulated adiponectin (1.47, p < 0.045) in the Le rats. The RE also induced phase I and phase II gene expression and the peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha. Notably, the RE decreased adipose phosphorylated AMP‐activated protein kinase and did not affect hepatic peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha in the Ob rats. CONCLUSION: Our results show that an RE rich in CA exerts anti‐inflammatory effects and affects hepatic metabolism in normal Le rats. We report significant differences in the expression and regulation of key metabolic sensors between Le and Ob rats that may contribute to explain the different ability of the two genotypes to respond to the RE.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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