Ellagic Acid and Polyhydroxylated Urolithins Are Potent Catalytic Inhibitors of Human Topoisomerase II: An in Vitro Study

Furlanetto, Valentina; Zagotto, Giuseppe; Pasquale, Riccardo; Moro, Stefano; Gatto, Barbara

doi:10.1021/jf302600q

Cited by 27 publications

(20 citation statements)

References 52 publications

(100 reference statements)

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“…A particularly important capacity attributed to Uro-A and Uro-B is that of inhibiting quorum sensing through the modulation of gene expression in Yersinia enterocolitica [63], showing for the first time the ability of these gut microbiota metabolites to interfere with enteropathogens and supporting that the ET metabolites may have an effect on infections and microbial populations in the gut [60]. Urolithins also appear to inhibit hyaluronidase [105], topoisomerase [106], and cholinesterase [107] activities, adding more tentative targets for these metabolites within the cells. However, the translation of these in vitro results to in vivo context is far from proven.…”

Section: Miscellaneous Effectsmentioning

confidence: 95%

Urolithins, the rescue of “old” metabolites to understand a “new” concept: Metabotypes as a nexus among phenolic metabolism, microbiota dysbiosis, and host health status

Tomás-Barberán

González‐Sarrías

Garcı́a-Villalba

et al. 2016

Molecular Nutrition Food Res

354

384

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Urolithins are dibenzo[b,d]pyran-6-one derivatives that are produced by the human gut microbiota from ellagitannins and ellagic acid (EA). These metabolites are much better absorbed than their precursors and have been suggested to be responsible for the health effects attributed to ellagitannins and EA that occur in food products as berries and nuts. In the present review, the role and potential of urolithins in human health are critically reviewed, and a perspective of the research approach needed to demonstrate these health effects is presented, based on the existing knowledge. The analytical methods available for urolithin analysis, their occurrence in different tissues and biological fluids, and their metabolism by human gut microbiota are considered. In addition, the interindividual variability observed for the production of urolithins (metabotypes) and its relationship with health status and dysbiosis are also reviewed. The potential mechanisms of action of urolithins are also critically discussed, paying attention to the concentration and the type of metabolites used in the in vitro and in vivo assays and the physiological significance of the results obtained. The gut microbiota metabolism of EA to urolithins and that of daidzein to equol, their individual variations, and the effects on health are also compared.

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Section: Miscellaneous Effectsmentioning

confidence: 95%

Urolithins, the rescue of “old” metabolites to understand a “new” concept: Metabotypes as a nexus among phenolic metabolism, microbiota dysbiosis, and host health status

Tomás-Barberán

González‐Sarrías

Garcı́a-Villalba

et al. 2016

Molecular Nutrition Food Res

354

384

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“…Urolithin M5 and another synthetic urolithin (never detected as an ellagic acid or ellagitannin metabolite in animals) showed topoisomerase inhibitory activity at concentrations below 1 μ M, showing an even more potent activity than that of the chemotherapeutic drug doxorubicin. The molecular mechanism of action toward human topoisomerase II seems to be the competition with ATP for the ATP binding pocket of the human enzyme [55]. …”

Section: Biological Activity Of Urolithinsmentioning

confidence: 99%

Biological Significance of Urolithins, the Gut Microbial Ellagic Acid-Derived Metabolites: The Evidence So Far

Espı́n

Larrosa

Garcı́a-Conesa

et al. 2013

Evidence-Based Complementary and Alternative Medicine

451

430

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The health benefits attributed to pomegranate have been associated with its high content in polyphenols, particularly ellagitannins. This is also the case for other ellagitannin-containing fruits and nuts including strawberry, raspberry, blackberry, walnuts, and muscadine grapes. The bioavailability of ellagitannins and ellagic acid is however very low. These molecules suffer extensive metabolism by the gut microbiota to produce urolithins that are much better absorbed. Urolithins circulate in plasma as glucuronide and sulfate conjugates at concentrations in the range of 0.2–20 μM. It is therefore conceivable that the health effects of ellagitannin-containing products can be associated with these gut-produced urolithins, and thus the evaluation of the biological effects of these metabolites is essential. Recent research, mostly based on in vitro testing, has shown preliminary evidence of the anti-inflammatory, anticarcinogenic, antiglycative, antioxidant, and antimicrobial effects of urolithins, supporting their potential contribution to the health effects attributed to pomegranate and ellagitannin-rich foods. The number of in vivo studies is still limited, but they show preventive effects of urolithins on gut and systemic inflammation that encourage further research. Both in vivo and mechanistic studies are necessary to clarify the health effects of these metabolites. Attention should be paid when designing these mechanistic studies in order to use the physiologically relevant metabolites (urolithins in gut models and their conjugated derivatives in systemic models) at concentrations that can be reached in vivo.

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“…However, polyphenol absorption is reportedly very low. Urolithins are the major metabolites of polyphenols in the gut . We isolated and purified urolithins from the intestinal metabolites of pomegranate ellagitannins by high‐speed counter‐current chromatography .…”

Section: Introductionmentioning

confidence: 99%

“…Urolithins are the major metabolites of polyphenols in the gut. [23][24][25] We isolated and purified urolithins from the intestinal metabolites of pomegranate ellagitannins by high-speed counter-current chromatography. 26 Urolithins can be absorbed by multiple tissue types and can suppress tumorigenesis, 27 oxidation, 28 inflammation, [29][30][31] and microbial 32 activity in vitro.…”

Section: Introductionmentioning

confidence: 99%

Metabolite of ellagitannins, urolithin A induces autophagy and inhibits metastasis in human sw620 colorectal cancer cells

Zhao

Shi

Guo

et al. 2017

Molecular Carcinogenesis

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Autophagy is an evolutionarily conserved pathway in which cytoplasmic contents are degraded and recycled. This study found that submicromolar concentrations of urolithin A, a major polyphenol metabolite, induced autophagy in SW620 colorectal cancer (CRC) cells. Exposure to urolithin A also dose‐dependently decreased cell proliferation, delayed cell migration, and decreased matrix metalloproteinas‐9 (MMP‐9) activity. In addition, inhibition of autophagy by Atg5‐siRNA, caspases by Z‐VAD‐FMK suppressed urolithin A‐stimulated cell death and anti‐metastatic effects. Micromolar urolithin A concentrations induced both autophagy and apoptosis. Urolithin A suppressed cell cycle progression and inhibited DNA synthesis. These results suggest that dietary consumption of urolithin A could induce autophagy and inhibit human CRC cell metastasis. Urolithins may thus contribute to CRC treatment and offer an alternative or adjunct chemotherapeutic agent to combat this disease.

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Ellagic Acid and Polyhydroxylated Urolithins Are Potent Catalytic Inhibitors of Human Topoisomerase II: An in Vitro Study

Cited by 27 publications

References 52 publications

Urolithins, the rescue of “old” metabolites to understand a “new” concept: Metabotypes as a nexus among phenolic metabolism, microbiota dysbiosis, and host health status

Urolithins, the rescue of “old” metabolites to understand a “new” concept: Metabotypes as a nexus among phenolic metabolism, microbiota dysbiosis, and host health status

Biological Significance of Urolithins, the Gut Microbial Ellagic Acid-Derived Metabolites: The Evidence So Far

Metabolite of ellagitannins, urolithin A induces autophagy and inhibits metastasis in human sw620 colorectal cancer cells

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