Mechanism Of Ellagic Acid Research Articles

Protective effects and mechanisms of ellagic acid on intestinal injury in piglets infected with porcine epidemic diarrhea virus.

The present study was conducted to decipher the protection effects of ellagic acid (EA) on piglets infected with porcine epidemic diarrhea virus (PEDV). Thirty 7-day-old piglets were randomly assigned to three treatment groups: control, PEDV, and EA + PEDV groups. After a 3-day period of adaption, piglets in the EA + PEDV group were orally administered with 20 mg/kg·BW EA during days 4-11 of the trial. On day 8, piglets were orally administered with PEDV at a dose of 106 TCID50 (50% tissue culture infectious dose) per pig. Additionally, intestinal porcine epithelial (IPEC-1) cells infected with PEDV were used to investigate the anti-PEDV effect of EA in vitro. The results showed that EA at a dose of 10-40 μmol/L increased the viability of PEDV-infected IPEC-1 cells, and EA administration mitigated intestinal edema in piglets challenged with PEDV. Further studies indicated that EA treatment significantly increased the proportion of white blood cells in blood and concentrations of IL-6, IL-1β, and IL-10 in the serum, but decreased the TNF-α content and gene expression of IL-6, IL-1β, TNF-α, and CXCL2 in the jejunum. Moreover, EA intervention considerably elevated the activity of total superoxide dismutase (T-SOD), but decreased the H2O2 concentration in the ileum of piglets. Importantly, EA suppressed the increased expression of antiviral-related genes and proteins (including MXI, ISG15, HSP70, and p-IRF7) induced by PEDV challenge in the jejunum. Furthermore, PEDV infection increased the protein abundance of p-JAK2 and p-STAT3, which were further enhanced by EA supplementation. In conclusion, our results revealed that EA could promote the restoration of intestinal homeostasis by regulating the interferon pathway that was interrelated with the activation of JAK2/STAT3 signaling. These findings provide theoretical basis for the use of EA as a therapy targeting PEDV infection in piglets.

Ellagic acid alleviates TNBS-induced intestinal barrier dysfunction by regulating mucin secretion and maintaining tight junction integrity in rats

In the present study, the mechanism of ellagic acid (EA) in alleviated ulcerative colitis (UC) was investigated. Twenty-four SD rats were randomly distributed into three treatment groups: (1) control group, (2) UC group, and (3) UC + EA group. Samples were collected for analysis after a 15-day trial period. We found that EA mitigated the colitis symptoms in TNBS-treated rats. Besides, EA decreased the expression of cytokines by inhibiting NF-κB signalling. TNBS-induced reduction in tight junction proteins was restored by EA supplementation via regulating RhoA/ROCK/MLC signalling. Further, persistent colonic inflammation destroyed the activity of goblet cells by inhibiting the expression of KLF4 and TFF3. EA also enhanced the expression of MUC2, AGR2, ST6GAL1 and B3GNT6. In summary, our findings demonstrated that dietary supplementation with EA ameliorated TNBS-induced colitis by maintaining intestinal barrier function, which proves its potential role as a therapeutic agent in the attenuation of UC.

Xanthine oxidase inhibitory kinetics and mechanism of ellagic acid: In vitro, in silico and in vivo studies.

Ellagic acid (EA), which is widely distributed in many foods, has been found to possess inhibitory activity against xanthine oxidase (XO). However, there is ongoing debate about the difference in XO inhibitory activity between EA and allopurinol. Additionally, the inhibitory kinetics and mechanism of EA on XO are still unclear. Herein, the authors systematically studied the inhibitory effects of EA on XO. The authors' findings showed that EA is a reversible inhibitor with mixed-type inhibition, and its inhibitory activity is weaker than allopurinol. Fluorescence quenching experiments suggested that the generation of EA-XO complex was exothermic and spontaneous. In silico analysis further confirmed that EA entered the XO catalytic centre. Furthermore, the authors verified the anti-hyperuricemia effect of EA in vivo. This study elucidates the inhibition kinetics and mechanism of EA on XO, and lays a theoretical foundation for the further development of drugs and functional foods containing EA for the treatment of hyperuricemia.

The Potential Antipyretic Mechanism of Ellagic Acid with Brain Metabolomics Using Rats with Yeast-Induced Fever.

Fever is caused by an increase in the heat production process when the body is under the action of a heat source or the dysfunction of the temperature center. Ellagic acid (EA) is a polyphenol dilactone that has anti-inflammatory, anti-tumor, and antioxidant activities. Male Sprague-Dawley rats were injected yeast to reproduce an experimental fever model (150 ± 20 g), and the rectal temperature and its change values were subsequently taken 19 h later; the excessive production of interleukin-1β (IL-1β) and prostaglandin2 (PGE2) induced by yeast was regulated to normal by EA administration. Rat brain metabolomics investigation of pyrexia and the antipyretic anti-inflammatory effect of EA was performed using Ultra-High-Performance Liquid Chromatography–Mass spectrometry (UPLC-MS). Twenty-six metabolites, as potential biomarkers, significantly altered metabolites that were found in pyretic rats, and eleven metabolites, as biomarkers of the antipyretic mechanism of EA, were significantly adjusted by EA to help relieve pyrexia, which was involved in glycerophospholipid metabolism and sphingolipid metabolism, etc. In conclusion, potential metabolic biomarkers in the brain shed light on the mechanism of EA’s antipyretic effects, mainly involving metabolic pathways, which may contribute to a further understanding of the therapeutic mechanisms of fever and therapeutic mechanism of EA.

The bioactivity and applications of pomegranate peel extract: A review.

Pomegranate peel (PP) is a by-product in the processing of pomegranate products, which is usually discarded as a waste. However, a large number of researches have shown that pomegranate peel extract (PPE) is rich in a variety of phenolic substances, among which ellagic acid (EA), as one of the main active components, has significant biological activities, such as anti-oxidation, anti-tumor, anti-inflammatory, neuroprotection, anti-viral, and anti-bacterial. We analyzed the mechanism of EA's biological activity, and discussed its application in the food industry, for instance, food preservation, food additives, and functional foods. Combined with the research status of PPE, we discussed the limitations and development potential of PPE, in order to provide theoretical reference and scientific basis for the development and utilization of pomegranate by-products. PRACTICAL APPLICATIONS: Pomegranate peel (PP), the inedible part of the fruit, is usually treated as waste. In recent years, researchers have been committed to exploring various bioactive ingredients in PP and exploring its potential benefits to human health, which has far-reaching significance. In this paper, the chemical constituents of polyphenols in PP were reviewed, mainly focusing on the biological activity and mechanism of ellagic acid (EA). We reviewed the applications and invention patents of pomegranate peel extract (PPE) in food field, including food preservation, food additive, and functional foods, providing reference for the recycling and reuse of PP.

Ellagic Acid Attenuates BLM-Induced Pulmonary Fibrosis via Inhibiting Wnt Signaling Pathway.

Idiopathic pulmonary fibrosis is a progressive lung disease with high mortality and limited therapy that is characterized by epithelial cell damage and fibroblast activation. Ellagic acid is a natural polyphenol compound widely found in fruits and nuts that has multiple pharmacological activities. In this study, we explored the potential effects and mechanisms of Ellagic acid on pulmonary fibrosis in vivo and in vitro. In vivo studies showed that Ellagic acid significantly alleviated bleomycin (BLM)-induced pulmonary fibrosis in mice. In vitro experiments indicated that Ellagic acid could suppress Wnt signaling and attenuate Wnt3a-induced myofibroblast activation and the phosphorylation of Erk2 and Akt. Further studies showed that Ellagic acid could induce autophagy formation in myofibroblasts mainly by suppressing mTOR signaling and promoting apoptosis of myofibroblasts. In vivo experiments revealed that Ellagic acid significantly inhibited myofibroblast activation and promoted autophagy formation. Taken together, our results show that Ellagic acid effectively attenuates BLM-induced pulmonary fibrosis in mice by suppressing myofibroblast activation and promoting autophagy and apoptosis of myofibroblasts by inhibiting the Wnt signaling pathway.

The effect and mechanism of ellagic acid on the proliferation and invasion properties of human glioma U251 cells

Objective To investigate the anti-proliferation and anti-metastatic effect of ellagic acid (EA) on glioma cell line U251 and related mechanisms. Methods In this study, we employed cell counting kit-8 (CCK-8) assay to test the anti-proliferative effect of EA. Flow cytometer was used to monitor cell apoptosis and cell cycle. Wound healing assay and Transwell assay were used to test the anti-invasion effect of EA. Western blotting was employed to test the effect of EA on the expressions of B cell lymphoma/leukemia-2 (bcl-2), bcl-2 associated X protein (bax), Cysteinyl aspartate-specific protease (Caspase)-3, matrix metalloproteinase (MMP)-9 and MMP-2. Results EA could significantly inhibit the proliferation of U251 cells in concentration-dependent manner and time-dependent manner, and the concentration of half maximal inhibitory concentration (IC50) after treated 48 hours was 39.24 μg/ml. The apoptosis rate of 40 μg/ml was (34.07±0.28)%, compared with control group, the difference was significant (P=0.001). Flow cytometer test shows the percentage of cells in S phase treated by EA 40 μg/ml was (47.75±2.02)%, compared with control group (20.45±0.28)%, the difference was significant (P=0.000). The expressions of bax and Caspase-3 were increased significantly, while bcl-2 was decreased. In Wound healing assay, when treated 24 h by EA, the wound healing rate in control group, 5 μg/ml group, 10 μg/ml group were (53.88±0.30)%, (36.82±0.56)% and (31.33±0.24)%, the difference was significant (P=0.000, P=0.000); In Transwell assay, the number of passed cells were (168.2±7.1), (66.4±2.5) and (38.6±1.5) respectively, the difference was significant (P=0.001, P=0.000). The expressions of MMP-9 and MMP-2 were decreased significantly. Conclusion EA inhibits the proliferation and invasion of glioma cell line U251, which suggests that EA is a potential therapeutic agent for glioma. Key words: Glioma; Ellagic acid; Proliferation; Invasion; U251 cells

Study on effect and mechanism of ellagic acid on the proliferation and apoptosis of pancreatic cancer cell line PANC-1

Objective To investigate the effect of ellagic acid on the proliferation and apoptosis of pancreatic cell line PANC-1 in vitro and explore possible mechanism of ellagic acid's effect on PANC-1 cells. Methods PANC-1 cells were treated with ellagic acid at concentrations of 0, 2, 4, 6, 8 μg/ml for 24, 48 and 72 h respectively. Inverted Microscope showed cells' morphological changes. The cell proliferation was determined by methyl thiazolyl tetrazolium (MTT) assay. When the cells were treated with ellagic acid at concentrations of 0, 2, 4, 6 μg/ml for 48 h, the morphological changes of apoptotic cells were observed by cell staining, apoptotic rate and cell cycle were detected by flow cytometry, the protein expression of cyclo-oxgenase 2 (COX-2) and nuclear factor-κB (NF-κB) were measured by Western blotting. Results Ellagic acid could significantly inhibited the growth of PANC-1 cells in a concentration-dependent and time-dependent manner. The difference among these groups were statistically significant(P<0.05). After treatment with ellagic acid, apoptosis of PANC-1 cells was seen. Apoptosis rates in the different concentration groups were respectively (11.18±0.99)%, (20.70±2.32)%, (39.68±0.69)%, the apoptosis rate of control group [(0.62±0.23)%] compared with statistically significant difference among the different concentration groups (P<0.05). The percentages of G0/G1 phase cells were respectively(48.98±2.36)%, (60.80±1.40)%, (72.82±0.59)%, the percentage of control group [(42.78±0.74)%] compared with statistically significant difference among the different concentration groups(P<0.05). The protein expression of COX-2 and NF-κB measured by Western blotting were significantly down-regulated dose-dependently. Conclusion Ellagic acid can inhibit the proliferation of pancreatic cancer cell line PANC-1 and induce apoptosis. The mechanism may depend on arresting cell cycle and decreasing protein expression of COX-2 and NF-κB. Key words: Ellagic acid; Pancreatic neoplasm; Proliferation; Apoptosis; Cyclo-oxgenase 2; Nuclear factor-κB

Research progress on the anticarcinogenic actions and mechanisms of ellagic acid.

Cancer is a leading cause of death worldwide. Cancer treatments by chemotherapeutic agents, surgery, and radiation have not been highly effective in reducing the incidence of cancers and increasing the survival rate of cancer patients. In recent years, plant-derived compounds have attracted considerable attention as alternative cancer remedies for enhancing cancer prevention and treatment because of their low toxicities, low costs, and low side effects. Ellagic acid (EA) is a natural phenolic constituent. Recent in vitro and in vivo experiments have revealed that EA elicits anticarcinogenic effects by inhibiting tumor cell proliferation, inducing apoptosis, breaking DNA binding to carcinogens, blocking virus infection, and disturbing inflammation, angiogenesis, and drug-resistance processes required for tumor growth and metastasis. This review enumerates the anticarcinogenic actions and mechanisms of EA. It also discusses future directions on the applications of EA.