CK2 ( IC50 = 40 nM )

Ellagic acid (EA; 10 mg/kg/day; p.o., 14 days) significantly lowers brain MDA content by 17% and brain TNF-α levels by 42% in rats. Ellagic acid significantly raises the decreased levels of dopamine (DA, 71%) norepinephrine (NE, 77%) and 5-HT (39%). In rats, elastabic acid (10 mg/kg, p.o., 14 days) reduces the histopathological alterations brought on by doxorubicin[2].

The CK2 and CK1 phosphorylation tests are conducted at 37°C with increasing concentrations of each inhibitor (Ellagic acid) in a final volume of 25 µL that contains 50 mM, pH 7.5 Tris-HCl, 100 mM NaCl, 12 mM MgCl₂, and 0.02 mM [³³P-ATP] (500-1000 cpm/pmol), unless otherwise specified. For CK1 and CK2, the phosphorylatable substrates are RRKHAAIGDDDDAYSITA (200 µM) and RRRADDSDDDDD (100 µM), respectively, synthetic peptide substrates. The kinase was added first, and after 10 minutes, the reaction was stopped by adding 5 µL of 0.5 M orthophosphoric acid. This was done before aliquots were placed onto phosphocellulose filters. After the radiolabeled samples are separated by SDS-PAGE, filters are cleaned in a 75 mM phosphoric acid substrate. The tyrosine kinase activities of DYRK1A are measured using the peptide RRRFRPASPLRGPPK[1].

MTT assay is used to determine ALCL cell viability. In short, 12 hours before adding ellagic acid, 0.1 × 10⁵ cells are seeded onto 96-well microculture plates. The cells are cultured in 200 µL of full RPMI-1640 medium for 48 hours, either with or without the medication (elagic acid), following standard tissue-culture procedures. Next, add 20 µL of MTT solution (5 mg/mL) to the cell suspension and let it sit for 4 hours. 150 µL of DMSO is used to dissolve the intracellular formazan crystals, and the optical density—which is determined at 540 nm using a spectrophotometer—represents the average (± SD) of three replicate cultures[1].

Fifty adult male Sprague-Dawley rats are split into five groups at random, which are as follows: As a vehicle and standard control, Group (1) is given oral corn oil. Doxorubicin (DOX) injections (5 mg/kg, i.p.) are given to Group (2) twice a week for a duration of 14 days. For a duration of 14 days, Group 3 is administered Ellagic acid (10 mg/kg, p.o.; daily) and DOX (5 mg/kg, i.p.) twice a week. For 14 days, rosmarinic acid (RA; 75 mg/kg, p.o.; daily) and DOX (5 mg/kg, i.p.) are given to Group 4. For a duration of 14 days, Group 5 is administered Ellagic acid (10 mg/kg, p.o.; daily) along with RA (75 mg/kg, p.o.; daily) and a DOX injection (5 mg/kg, i.p.) twice a week[2].

Absorption, Distribution and Excretion
After oral consumption, ellagic acid reaches maximum concentrations in about 1 hour.
Ellagic acid is eliminated from the body in about 4 hours.
The present study was initiated to determine ... the distribution of (14)C-ellagic acid (EA) and (3)H-N-methyl-N-nitrosourea (MNU) in the rat whole embryo culture model system ... (14)C-EA (50 uM for 2 hr, known embryoprotective concentration; no MNU added) was used to demonstrate access of EA to the embryo within the 2 hr exposure period. The majority of EA (99.5%) remained in the media while tissue concentrations of 57.0 and 47.9 pmol/mg were attained in the yolk sacs and embryos, respectively.
Ellagic acid (EA), derived from fruit ellagitannins, is known to be antimutagenic and anticarcinogenic in various animal tumor models. In this study, EA at a dose of 4 g/kg diet inhibited multiplicity of tumors induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in A/J mice by 54%. This inhibition was dose related between 0.06 and 4.0 g/kg diet. In contrast, two related compounds, esculin and esculetin, had no effect on lung tumorigenesis. The biodistribution of ellagic acid (EA) /in A/J mice/ was studied as a function of dose and time after gavage of EA. The levels of EA in the lung were directly proportional to the dose of EA between 0.2 and 2.0 mmol. The maximum level of EA, corresponding to 21.3 nmol/g, was observed 30 minutes after gavage with 2.0 mmol of EA/kg body wt, which corresponds to only 70 ppm of the administered dose. The levels in liver tissues were 10-fold lower and reached a maximum 30 minutes after gavage. At this interval, the blood level of EA was 1 nmol/mL. The inclusion of EA in cyclodextrin doubles the level of EA in lung tissues. These results demonstrate that EA localizes preferentially in lung tissues ...
... Ellagic acid (EA), a dietary antioxidant associated with poor biopharmaceutical properties, was encapsulated into poly(lactide-co-glycolide) (PLGA) and polycaprolactone (PCL) nanoparticles to improve oral bioavailability ... The antioxidant potential of the didodecyldimethyl ammonium bromide (DMAB)-stabilized nanoparticulate formulations was evaluated against cyclosporine A (CyA)-induced nephrotoxicity in rats ... From in situ permeation studies in rats, it was evident that intestinal uptake of EA as DMAB-stabilized nanoparticles was significantly higher as compared to the sodium carboxymethyl cellulose suspension and the polyvinyl alcohol (PVA)-stabilized particles. EA and EA nanoparticles were able to prevent the CyA-induced nephrotoxicity in rats as evident by biochemical parameters as well as kidney histopathology.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Pomegranate juice contains ellagitannins and numerous polyphenols such as delphinidin, cyanidin, pelargonidin, punicalin, pedunculagin, punicalagin, gallagic, and ellagic acid as well as vitamin C and B vitamins. Administration of pomegranate juice to nursing mothers result in a change in the microbiota of breastmilk and infant stools and an increase in antioxidant content of breastmilk and infant urine. A low-quality study found that administration of pomegranate juice concentrate to nursing mothers of infants with hyperbilirubinemia hastened the infant’s improvement with phototherapy treatment. No adverse reactions to maternal pomegranate ingestion in breastfed infants have been observed.
◉ Effects in Breastfed Infants
Twelve exclusively breastfeeding mothers of full-term infants consumed 8 fluidounces of pomegranate juice daily for 2 weeks. After 2 weeks, the infant stool samples had significant increases in the abundance of bacteria from the phylum Firmicutes (genus Lachnoclostridium and Staphylococcus). Infants whose mothers’ milk contained urolithin B-glucuronide (metabotype B) showed significant differences in 4 bacteria, with 2 bacteria from the phyla Firmicutes (genus Veillonella) and Bacteroidetes (genus Bacteroides and Parabacteroides) and Bifidobacterium. Infant stool Blautia was positively corelated with breastmilk and plasma urolithin B-glucuronide and infant stool Enterococcus was inversely related to breastmilk maternal plasma urolithin B-glucuronide, and maternal plasma urolithin B-glucuronide and dimethyl ellagic acid glucuronide.
An open-label, nonblinded study randomized mothers of newborn infants to receive either concentrated pomegranate juice 15 mL 3 times daily or nothing (i.e., no placebo control). There were 43 mother-infant pairs in each group. The concentrate was made from the juice of fresh pomegranates concentrated at a warm temperature to a Brix of 60%. The total phenol content was 13.56 mg/g and the total flavonoid was 1.39 mg/g. All of the infants were over 72 hours old, had a gestational age over 37 weeks and birth weight over 2500 grams. Both groups were being treated with phototherapy for hyperbilirubinemia (total serum bilirubin level over 15 mg/dL). There was a greater decrease in bilirubin levels in the pomegranate group at 48 and 72 hours after the start of phototherapy and at 48 hours after discharge. In addition, the mean duration of phototherapy in the pomegranate group was significantly shorter (52 hours compared to 65 hours) than in the no-pomegranate group. All infants in the pomegranate group were discharged by 96 hours after the start of treatment compared to 114 hours in the no-pomegranate group. No side effects were observed in the infants whose mothers received pomegranate juice concentrate.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Interactions
Naturally occurring plant phenols with antimutagenic and anticarcinogenic activities were tested for their abilities to inhibit the biochemical and biological effects of the potent tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA) in mouse epidermis in vivo. When applied topically to mouse skin, tannic acid (TA), ellagic acid, and several gallic acid derivatives all inhibit TPA-induced ornithine decarboxylase activity, hydroperoxide production, and DNA synthesis, three biochemical markers of skin tumor promotion. Moreover, in the two-step initiation-promotion protocol, the same phenolic compounds also inhibit the incidence and yield of skin tumors promoted by TPA.
Resveratrol is shown to have a synergistic effect in vitro with both quercetin and ellagic acid for apoptosis ...
... Ellagic acid (EA) at a dose of 4 g/kg diet inhibited multiplicity of tumors induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in A/J mice by 54%. This inhibition was dose related between 0.06 and 4.0 g/kg diet ...
When administered in a semi-purified diet at concentrations of 0.4 and 4 g/kg, ellagic acid (EA) produced a significant (21 to 55%) decrease in the average number of N-nitrosobenzylmethylamine (NBMA)-induced esophageal tumors after 20 and 27 weeks of the bioassay. EA exhibited inhibitory effects toward preneoplastic lesions as well as neoplastic lesions. Tumors were not observed in vehicle-control rats or in rats that received EA alone.
For more Interactions (Complete) data for ELLAGIC ACID (6 total), please visit the HSDB record page.

[1]. Identification of ellagic acid as potent inhibitor of protein kinase CK2: a successful example of a virtual screening application. J Med Chem. 2006 Apr 20;49(8):2363-6.

[2]. Prophylactic effects of ellagic acid and rosmarinic acid on doxorubicin-induced neurotoxicity in rats. J Biochem Mol Toxicol. 2017 Dec;31(12).

[3]. Ellagic Acid Enhances Apoptotic Sensitivity of Breast Cancer Cells to γ-Radiation. Nutr Cancer. 2017 Aug-Sep;69(6):904-910.

[4]. Discovery of ellagic acid as a competitive inhibitor of Src homology phosphotyrosyl phosphatase 2 (SHP2) for cancer treatment: In vitro and in silico study. Int J Biol Macromol. 2023 Nov 5;254(Pt 2):127845.

Therapeutic Uses
/EXPL THER/ Italian researchers found that ellagic acid seemed to reduce the side effects of chemotherapy in men with advanced prostate cancer, although it did not help slow disease progression or improve survival.
/EXPL THER/ Ellagic acid seems to have some anti-cancer properties. It can act as an antioxidant, and has been found to cause apoptosis (cell death) in cancer cells in the lab. In other lab studies, ellagic acid seems to reduce the effect of estrogen in promoting growth of breast cancer cells in tissue cultures. There are also reports that it may help the liver to break down or remove some cancer-causing substances from the blood. Some supporters have claimed these results mean that ellagic acid can prevent or treat cancer in humans. This has not been proven. Unfortunately, many substances showing promise against cancer in lab and animal studies have not been found to be useful in people. Ellagic acid has also been said to reduce heart disease, birth defects, liver problems, and to promote wound healing. The available scientific research does not support these claims at this time.
/EXPL THER/ ... Ellagic acid (EA) at a dose of 4 g/kg diet inhibited multiplicity of tumors induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in A/J mice by 54%. This inhibition was dose related between 0.06 and 4.0 g/kg diet ...
/EXPL THER/ When administered in a semi-purified diet at concentrations of 0.4 and 4 g/kg, ellagic acid (EA) produced a significant (21 to 55%) decrease in the average number of N-nitrosobenzylmethylamine (NBMA)-induced esophageal tumors after 20 and 27 weeks of the bioassay. EA exhibited inhibitory effects toward preneoplastic lesions as well as neoplastic lesions. Tumors were not observed in vehicle-control rats or in rats that received EA alone.
/EXPL THER/ Ellagic acid inhibited lung tumorigenesis induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in A/J mice. This inhibition was related to the logarithm of the dose of ellagic acid added to the diet. The biodistribution of ellagic acid was studied in mice gavaged with ellagic acid. Pulmonary levels of ellagic acid were directly proportional to the dose of ellagic acid between 0.2 and 2.0 mmol/kg ...

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Drug Warnings
Ellagic acid is available in supplement form, but it has not been tested for safety. Some reports indicate it may affect certain enzymes in the liver, which could alter levels of some drugs in the body. For this reason, people taking medicines or other dietary supplements should talk with their doctors or pharmacists about all their medicines and supplements before taking ellagic acid. The raspberry leaf, or preparations made from it, should be used with caution during pregnancy because they may initiate labor.

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Pharmacodynamics
Ellagic acid's therapeutic action mostly involves antioxidant and anti-proliferative/anti-cancer effects.

C14H6O8

302.19

302.006

C, 55.64; H, 2.00; O, 42.35

476-66-4

133039-73-3;314041-08-2

5281855

Light yellow to khaki solid powder

2.1±0.1 g/cm3

796.5±60.0 °C at 760 mmHg

≥350 °C

310.1±26.4 °C

0.0±2.9 mmHg at 25°C

1.895

0.52

4

8

0

22

475

0

O1C(C2=C([H])C(=C(C3=C2C2=C1C(=C(C([H])=C2C(=O)O3)O[H])O[H])O[H])O[H])=O

AFSDNFLWKVMVRB-UHFFFAOYSA-N

InChI=1S/C14H6O8/c15-5-1-3-7-8-4(14(20)22-11(7)9(5)17)2-6(16)10(18)12(8)21-13(3)19/h1-2,15-18H

6,7,13,14-tetrahydroxy-2,9-dioxatetracyclo[6.6.2.04,16.011,15]hexadeca-1(15),4,6,8(16),11,13-hexaene-3,10-dione

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)