Ellagic acid is a natural phenolic antioxidant which is widespread in pomegranate, strawberry, blackberry and other fruits. It exists as a concentrated form, the ellagic tannin. Human and animal experiments indicated that ellagic tannin and ellagic acid have bioactivity of oxidation resistance, anti-inflammatory, anticancer and regulation of intestinal flora. It is potentially beneficial for prevention and treatment of cancer, diabetes, cardic-ceebrovascular diseases and nervous pathological changes.(Seeram, 2006)

However, the bioavailability of ellagic acid and ellagic tannin is extremely low. The concentration of ellagic acid disturbed in blood and organization is lower than the concentration of biological effect. In the intestine of mammals, some unabsorbed ellagic acid is metabolized into urolithins which is easier to be absorbed. (Cerda, 2003)

So the report shows urolithins may be the material bases of ellagic acid and ellagic tannin to exert bioactivity in vivo. (Larrosa, 2010)

1. Antioxidant activity 

Oxygen radical absorbance capacity experiments show, urolithin metabolites have a certain antioxidant activity, and Uro A has the strongest antioxidant activity. (Larrosa, 2010)

Uro A is able to substantially reduce malodialdehyde and relative oxygen species of human unitary bladder carcinoma T24 cells leaded by H2O2. And it can enhance the activities of superoxide dismutase. (Qiu, 2013)

In recent research, urolithin not only has anti-oxidation but also has pro-oxidation. Prof. Kallio found urolithin has strong anti-oxidation activity in oxygen radical absorbance capacity experiment, but has pro-oxidation in cell and copper-initiated pro oxidant activity experiment. (Kallio, 2013)

2. Anti-inflammatory activity 

Fibroblast cells play a major role in intestinal immunity. Urolithins can inhibit inflammatory reaction of fibroblast cells, which induced by interleukin-1beta(IL-1beta) or tumor necrosis factors-alpha(TNF-alpha). It can also reduce the expression level of prostag landin E2(PGE2).

UroA is able to inhibit the activation between nuclear transcription factor-κB and mitogen-activated protein kinases, which induced by IL-1beta and TNF-alpha. 

Glucuronolactone derivative of UroA may be the principal material in pomegranate juice to inhibit cardiovascular system inflammation. 

3. Anticancer activity 

The study in vivo shows, urolithin can inhibit cell reproduction of prostate cancer, colon cancer, and bladder cancer. The distribution of urolithin has obvious organizational characteristics, take an example, after intake of pomegranate juice, the metabolite-urolithin can be accumulated in prostatic tissue, so it may be used in treatment of prostatic diseases. (Blalonska, 2009)

Vicinanza found the metabolite of pomegranate-ellagic acid and UroA is able to inhibit the reproduction of prostate cancer cells relied on androgen. 

Metabolites of urolithin can inhibit the activity of protein kinase CK2 and topoisomerase II and other cancer related kinases, and it can also influence drug resistance of cancer cells. 

Breast cancer resistance protein(BCRP/ABCG2) is an essential protein to induce the drug resistance of cancer cells. It influences severely the chemotherapy effect. Gonzalez-Sarrias found, UroA and its disulfides derivatives can be the substrate of BCRP/ABCG2. (Gonzalez, 2013)

4. Regulator of estrogen receptor 

The unique molecular structure of UroA makes it easier to combine with alpha and beta estrogen receptor. (Larrosa, 2006) UroA is easier to be combined with estrogen alpha receptor. UroA can dose-independently promote the reproduction of breast cancer cell lines MCF-7. When the concentration is 40 μmol/, it will not inhibit the reproduction and show no cytotoxic effect. 

5. Inhibitory of heron glycation

Protein glycation end products are secondary effect of hyperglycemia, it is closely related to cardio-cerebral vascular diseases, diabetes and Alzheimer’s disease. (Dennis, 2013)

6. Regulation of intestinal flora

By the quorum sensing, intestinal flora produce and release some certain signals to exchange information, then it can regulate the group behaviors and gene expression. UroA is able to reduce the signal expression significantly. It can inhibit the formation and the process of movement related to quorum sensing. It means UroA can inhibit the growth of pathogens by quorum sensing, then keep the balance of intestinal flora. (Gimenez, 2012)

Tips:

In the cell anti oxidation experiment, the IC50 of UroA is 13.6 μmol/L. (Bialonska, 2009)

Ellagic acid and UroA in vivo can significantly inhibit the activity of protein kinase CK2, UroA’s IC 50 is 0,39 μmol/L.(Cozza, 2011)

Kasimsetty found that when the concentration of UroA is 25-50 μmol/L, it can induce the death of colon cancer cells HT-29, and when the concentration is 50-75 μmol/, it is able to inhibit the activity of 50% oxidase CYP1 of hun cytochrome P450. And it can induce cells arrest cycle. 

UroA can inhibit reproduction of bladder cancer T24 cells line when the IC50 is 43.9μmol/L. 

UroA(1μmol/L) can significantly inhibit proteins glycosylation.

Reference

Bialonska D, Kasimsetty S G, Khan S I, et al. Urolithins, intestinal microbial metabolites of Pomegranate ellagitannins, exhibit potent antioxidant activity in a cell-based assay.[J]. Journal of Agricultural & Food Chemistry, 2009, 57(21):10181-10186.

Cerdá B, Llorach R, Cerón J J, et al. Evaluation of the bioavailability and metabolism in the rat of punicalagin, an antioxidant polyphenol from pomegranate juice[J]. European Journal of Nutrition, 2003, 42(1):18-28.

Cozza G, Gianoncelli A, Bonvini P, et al. Urolithin as a converging scaffold linking ellagic acid and coumarin analogues: design of potent protein kinase CK2 inhibitors.[J]. Chemmedchem, 2011, 6(12):2273-86.

Dennis K E, Hill S, Rose K L, et al. Augmented Cardiac Formation of Oxidatively-Induced Carbonylated Proteins Accompanies the Increased Functional Severity of Post-Myocardial Infarction Heart Failure in the Setting of Type 1 Diabetes Mellitus[J]. Cardiovascular Pathology, 2013, 22(6):473-480.

Giménez-Bastida J A, Truchado P, Larrosa M, et al. Urolithins, ellagitannin metabolites produced by colon microbiota, inhibit Quorum Sensing, in Yersinia enterocolitica : Phenotypic response and associated molecular changes[J]. Food Chemistry, 2012, 132(3):1465-1474.

Gonzálezsarrías A, Miguel V, Merino G, et al. The Gut Microbiota Ellagic Acid-Derived Metabolite Urolithin A and Its Sulfate Conjugate Are Substrates for the Drug Efflux Transporter Breast Cancer Resistance Protein (ABCG2/BCRP)[J]. Journal of Agricultural & Food Chemistry, 2013, 61(18):4352-9.

Kallio T, Kallio J, Jaakkola M, et al. Urolithins display both antioxidant and pro-oxidant activities depending on assay system and conditions.[J]. Journal of Agricultural & Food Chemistry, 2013, 61(45):10720-9.

Larrosa M, Gonzálezsarrías A, Garcíaconesa M T, et al. Urolithins, Ellagic Acid-Derived Metabolites Produced by Human Colonic Microflora, Exhibit Estrogenic and Antiestrogenic Activities[J]. Journal of Agricultural & Food Chemistry, 2006, 54(5):1611-20.

Larrosa M, García-Conesa M T, Espín J C, et al. Ellagitannins, ellagic acid and vascular health[J]. Molecular Aspects of Medicine, 2010, 31(6):513-39.

Qiu Z, Zhou B, Jin L, et al. In vitro antioxidant and antiproliferative effects of ellagic acid and its colonic metabolite, urolithins, on human bladder cancer T24 cells[J]. Food & Chemical Toxicology An International Journal Published for the British Industrial Biological Research Association, 2013, 59(6):878-889.

Seeram N P, Heber D, Schulman R N. Pomegranates: ancient roots to modern medicine.[J]. Pomegranates Ancient Roots to Modern Medicine, 2006.