Gastrointestinal (GI) cancers are a significant global health concern with diverse etiologies and limited treatment options. Ellagic acid (EA), a natural polyphenolic compound, exhibits promising anticancer properties against various GI malignancies. In this article, we have reviewed recent research on the anticancer potential of EA across esophageal, gastric, colorectal, pancreatic, and liver cancers. In esophageal cancer, EA inhibits the formation of O6-methylguanine (O6-meGua) adducts induced by carcinogens like N-nitrosomethylbenzylamine (NMBA), thereby suppressing tumor growth. Additionally, EA inhibits STAT3 signaling and stabilizes tumor suppressor proteins, showing potential as an anti-esophageal cancer agent. In gastric cancer, EA regulates multiple pathways involved in cell proliferation, invasion, and apoptosis, including the p53 and PI3K-Akt signaling pathways. It also demonstrates anti-inflammatory and antioxidant effects, making it a promising therapeutic candidate against gastric cancer. In colorectal cancer (CRC), EA inhibits cell proliferation, induces apoptosis, and modulates the Wnt/β-catenin and PI3K/Akt pathways, suggesting its efficacy in preventing CRC progression. Furthermore, EA has shown promise in pancreatic cancer by inhibiting nuclear factor-kappa B, inducing apoptosis, and suppressing epithelial-mesenchymal transition. In liver cancer, EA exhibits radio-sensitizing effects, inhibits inflammatory pathways, and modulates the tumor microenvironment, offering potential therapeutic benefits against hepatocellular carcinoma. Studies on EA potential in combination therapies and the development of targeted delivery systems are required for enhanced efficacy against gastrointestinal cancers.

The dried ripe fruit of Terminalia chebula Retz. is a common Chinese materia medica, and ellagic acid (EA), isolated from the plant, is an important bioactive component for medicinal purposes. This study aimed to delineate the optimal extraction parameters for extracting the EA content from Chebulae Fructus (CF), focusing on the variables of ethanol concentration, extraction temperature, liquid-solid ratio, and extraction time. Utilizing a combination of the response surface methodology (RSM) and an artificial neural network (ANN), we systematically investigated these parameters to maximize the EA extraction efficiency. The extraction yields for EA obtained under the predicted optimal conditions validated the efficacy of both the RSM and ANN models. Analysis using the ANN-predicted data showed a higher coefficient of determination (R2) value of 0.9970 and a relative error of 0.79, compared to the RSM\'s 2.85. The optimal conditions using the ANN are an ethanol concentration of 61.00%, an extraction temperature of 77 °C, a liquid-solid ratio of 26 mL g-1 and an extraction time of 103 min. These findings significantly enhance our understanding of the industrial-scale optimization process for EA extraction from CF.

Walnuts (Juglans regia L.) are an important source of ellagitannins. They have been linked to positive effects on many pathologies, including cardiovascular disorders, neurodegenerative syndromes, and cancer. The limited bioavailability of ellagitannins prevents them from reaching significant circulatory levels, despite their antioxidant, anti-inflammatory, and chemopreventive properties. Urolithins are ellagitannin gut microbiota-derived metabolites. They have better intestinal absorption and may be responsible for the biological activities of ellagitannins. Recent evidence showed that walnut ellagitannins and their metabolites, urolithins, could have positive outcomes for human health. This study aims to synthesize the current literature on the antioxidant activity and mechanistic pathways involved in the therapeutic potential of walnut ellagitannins and their metabolites. In the eligible selected studies (n = 31), glansreginin A, pedunculagin, and casuarictin were the most prevalent ellagitannins in walnuts. A total of 15 urolithins, their glucuronides, and sulfate metabolites have been identified in urine, blood, feces, breast milk, and prostate tissue in analyzed samples. Urolithins A and B were associated with antioxidant, anti-inflammatory, cardioprotective, neuroprotective, anticarcinogenic, and anti-aging activities, both in preclinical and clinical studies. Despite the promising results, further well-designed studies are necessary to fully elucidate the mechanisms and confirm the therapeutic potential of these compounds in human health.

Fever is one of the most common clinical conditions and is characterized by pyrogenic infection, malignancy, inflammation, and tissue damage, among others. Ellagic acid (EA) can inhibit the expression of related proteins on the pathway by blocking the nuclear factor kappa-B(NF-κB) signaling pathway, inhibit the levels of pro-inflammatory factors interleukin-1β(IL-1β), interleukin-6(IL-6), and tumor necrosis factor-α(TNF-α), increase the level of anti-inflammatory factor IL-10, and effectively alleviate inflammatory symptoms. In addition, EA can also reduce the levels of malondialdehyde(MDA) and nitric oxide(NO) in the body, increase the activities of superoxide dismutase (SOD), glutathione (GSH), and catalase(CAT), scavenge oxidative free radicals, inhibit lipid oxidation, and achieve antipyretic and anti-inflammatory effects. The purpose of this study was to establish the relationship between EA and various inflammatory markers, such as TNF-α, IL-6, IL-1β, prostaglandin E2(PGE2), and cyclic adenosine monophosphate(cAMP), and clarify the mechanism of the cyclooxidase-2(COX-2)/NF-κB signaling pathway. Combined with the metabolomics analysis, our study revealed the effects of EA on multiple endogenous biomarkers, reflecting the characteristics of a multi-component, multi-target, and multi-pathway mechanism. Compared to lipopolysaccharide (LPS)- treated animals, subsequent administration of EA significantly lowered the LPS-induced rectal temperature increase (p < 0.05 or p < 0.01), significantly increased serum SOD and GSH levels (p < 0.05 or p < 0.01), and significantly decreased serum MDA, IL-1β, IL-6, and TNF-α levels (p < 0.05 or p < 0.01). In addition, compared to LPS-treated animals, subsequent administration of EA significantly decreased cerebrospinal fluid cAMP and PGE2 levels (p < 0.05 or p < 0.01), significantly decreased cAMP, significantly increased 5-HT levels (p < 0.05 or p < 0.01), and significantly down-regulated p-NF-κB p65 and COX-2 protein levels in the hypothalamus. Subsequent gas chromatography mass spectrometry(GC-MS) metabolite analysis indicated that 12 differential metabolites were detected in serum isolated 4 h after LPS treatment, and 10 differential metabolites were detected in serum collected 7 h after LPS treatment. Next, Pearson correlation analysis was used to systematically characterize the relationship between the identified metabolites and TNF-α, IL-6, MDA, SOD, PGE2, and cAMP. The levels of propionic acid, pyridine, and L-valine were up-regulated by EA, which inhibited the expression of MDA, IL-1β, and TNF-α and increased the activity of GSH. The levels of inositol, urea, and 2-monopalmitin were down-regulated by EA, which inhibited the expression of MDA, IL-1β, and TNF-α, increased the activity of SOD and GSH, reduced the inflammatory response, and alleviated the oxidative stress state. Combined with the results of the metabolic pathway analysis, we suggest that the pathways of the galactose metabolism, synthesis and degradation of ketone bodies, as well as ascorbic acid and aldehyde acid metabolism are closely related to the antipyretic and anti-inflammatory effects of EA. Our study established the relationship between EA and various inflammatory markers, such as TNF-α, IL-6, IL-1β, PGE2, and cAMP, and clarified the mechanism of the COX-2/NF-κB signaling pathway. Combined with the metabolomics analysis, our study revealed the effects of EA on multiple endogenous biomarkers, reflecting the characteristics of a multi-component, multi-target, and multi-pathway mechanism.

Osteoarthritis (OA) is a degenerative joint disease characterised by inflammation and cartilage degeneration. Ellagic acid (EA) might have therapeutic potential in OA, but its molecular mechanisms of action remain unclear. In this study, we aimed to identify the docking protein of EA in M1 macrophage-related pro-inflammation in OA. Bioinformatics analysis was performed to identify ellagic acid\'s potential targets among OA-related dysregulated genes. THP-1 cells were induced into M0 and polarised into M1 macrophages for in vitro studies. Mice knee models of OA were generated for in vivo studies. Results showed that PTGS2 (also known as COX-2) is a potential target of ellagic acid among OA-related dysregulated genes. EA has multiple low-energy binding sites on PTGS2, including sites containing amino acid residues critical for the enzyme\'s catalytic activity. Surface plasmon resonance (SPR) assays confirmed the physical interaction between ellagic acid and recombinant PTGS2 protein, with a dissociation constant (KD) of 5.03 ± 0.84 μM. EA treatment suppressed PTGS2 expression and prostaglandin E2 (PGE2) production in M1 macrophages. Besides, ellagic acid can directly inhibit PTGS2 enzyme activity, with an IC50 around 50 μM. Importantly, in a mouse model of OA, ellagic acid administration alleviated disease severity, reduced collagen II degradation and MMP13 generation, and decreased serum PGE2 levels. Collectively, these results suggest that PTGS2 is a key target of ellagic acid\'s anti-inflammatory and chondroprotective effects in OA.

The flavor stability of tea beverages during storage has long been a concern. The study aimed to explore the flavor stability of Longjing green tea beverage using accelerated heat treatment trials, addressing the shortage of lengthy storage trials. Sensory evaluations revealed changes in bitterness, umami, overall harmonization, astringency, and ripeness as treatment duration increased. Accompanied by a decrease in L-values, ΔE and an increase in a and b-values. Seventeen non-volatile metabolites and three volatile metabolites were identified differential among samples by metabolomics, with subsequent correlation analysis indicating associations between sensory attributes and specific metabolites. Umami was linked to epigallocatechin 3,5-digallate and alpha-D-glucopyranose, astringency was correlated with ellagic acid and 1-ethyl-1H-pyrrole. Ripeness showed associations with ellagic acid, 6,7-dihydroxycoumarin, heptanal, and benzaldehyde, and overall harmonization was linked to 6,7-dihydroxycoumarin, β-myrcene, α-terpineol, and heptanal. A series of verification tests confirmed the feasibility of accelerated heat treatment trials to replace traditional storage trials. These results offer valuable insights into unraveling the complex relationship between sensory and chemical profiles of green tea beverages.

This study explored the neuroprotective potential of fermented pomegranate (PG-F) against hydrogen peroxide (H2O2)-induced neurotoxicity in human neuroblastoma SH-SY5Y cells and elucidated the underlying molecular mechanisms. The fermentation process, involving probiotics, transforms the hydrolyzable tannins in pomegranate juice into ellagic acid (EA) and gallic acid (GA), which are believed to contribute to its health benefits. Molecular docking simulations confirmed the stable interactions between EA, GA, and proteins associated with the antioxidant and anti-apoptotic pathways. PG-F significantly enhanced the viability of H2O2-treated cells, as evidenced by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays, cell morphology observations, and Hoechst 33342 staining. PG-F mitigated the H2O2-induced intracellular reactive oxygen species (ROS) levels, restored mitochondrial membrane potential, and upregulated antioxidant gene expression. The PG-F treatment also attenuated the H2O2-induced imbalance in the Bax/Bcl-2 ratio and reduced the cleaved caspase-3, caspase-7, and caspase-9 levels, suppressing the apoptotic pathways. Further insights showed that PG-F inhibited the phosphorylation of mitogen-activated protein kinases (MAPKs) and facilitated the nuclear translocation of nuclear factor-erythroid 2-related factor (Nrf2), highlighting its role in modulating the key signaling pathways. A combined treatment with equivalent concentrations of EA and GA, as found in PG-F, induced remarkable cellular protection. Drug combination analysis using the Chou-Talalay method revealed a synergistic effect between EA and GA, emphasizing their combined efficacy. In conclusion, PG-F has significant neuroprotective effects against H2O2-induced neurotoxicity by modulating the antioxidant and anti-apoptotic pathways. The synergistic action of EA and GA suggests the therapeutic potential of PG-F in alleviating oxidative stress-associated neurodegenerative diseases.

Pomegranate polyphenol ellagic acid has medicinal potential in neurodegenerative disorders. The advantageous effect of this polyphenol in improving cognition in okadaic acid (OA)-instigated murine model with unraveling some modes of its action was assessed. Rats received ICV okadaic acid (OA) and post-treated with oral ellagic acid for 3 weeks (25 and 100 mg/kg/day). Cognition was analyzed in behavioral tasks besides assessment of oxidative, apoptotic, and inflammatory factors in addition to hippocampal histochemical analysis. Ellagic acid at a dose of 100 mg/kg properly attenuated cognitive abnormalities in novel object recognition (NOR), Y maze, and Barnes maze tests. Additionally, ellagic acid diminished hippocampal changes of malondialdehyde (MDA), protein carbonyl, reactive oxygen species (ROS), glutathione (GSH), glutathione peroxidase, superoxide dismutase (SOD), apoptotic factors caspases 1 and 3, tumor necrosis factor α (TNFα), and acetylcholinesterase (AChE) and beta secretase 1 (BACE 1) besides reversal of AMP-activated protein kinase (AMPK) and hyperphosphorylated tau (p-tau). Moreover, lower glial fibrillary acidic protein (GFAP) and less injury of hippocampal CA1 pyramidal neurons were observed upon ellagic acid. To conclude, neuroprotective potential of ellagic acid was shown which is somewhat attributable to its reversal of oxidative, apoptotic, and neuroinflammatory events in addition to proper regulation of AMPK and p-tau.

Arsenic, a neurotoxic metalloid, poses significant health risks. However, ellagic acid, renowned for its antioxidant properties, has shown potential in neuroprotection. This study aimed to investigate the neuroprotective effects of ellagic acid against arsenic-induced neuronal ferroptosis and cognitive impairment and elucidate the underlying mechanisms. Using an arsenic-exposed Wistar rat model and an arsenic-induced HT22 cells model, we assessed cognitive ability, measured serum and brain arsenic levels, and evaluated pathological damage through histological analysis and transmission electron microscopy. Additionally, we examined oxidative stress and iron ion levels using GSH, MDA, ROS and tissue iron biochemical kits, and analyzed the expression of ferroptosis-related markers using western blot and qRT-PCR. Our results revealed that arsenic exposure increased both serum and brain arsenic levels, resulting in hippocampal pathological damage and subsequent decline in learning and memory abilities. Arsenic-induced neuronal ferroptosis was mediated by the inhibition of the xCT/GSH/GPX4/Nrf2 signaling axis and disruption of iron metabolism. Notably, ellagic acid intervention effectively reduced serum and brain arsenic levels, ameliorated neuronal damage, and improved oxidative stress, ferroptosis, and cognitive impairment. These beneficial effects were associated with the activation of the Nrf2/Keap1 signaling pathway, upregulation of GPX4 expression, and enhanced iron ion excretion. In conclusion, ellagic acid demonstrates promising neuroprotective effects against arsenic-induced neurotoxicity by mitigating neuronal ferroptosis and cognitive impairment.

Ellagic acid (EA) is a phenolic phytochemical found in many plants and their fruits. Vaginal epithelial cells are the first line of defense against pathogen invasion in the female reproductive tract and express antimicrobial peptides, including hBD2 and SLPI. This study investigated the in vitro effects of EA (1) on vaginal innate immunity using human vaginal epithelial cells, and (2) on HPV16 pseudovirus infection. Vaginal cells were cultured in the presence or absence of EA, and the expression of hBD2 and SLPI was determined at both transcriptional and translational levels. In addition, secretion of various cytokines and chemokines was measured. Cytotoxicity of EA was determined by CellTiter-blue and MTT assays. To investigate the ability of EA to inhibit HPV16 infection, EA was used to treat HEK-293FT cells in pre-attachment and adsorption steps. We found significant increases in both hBD2 mRNA (mean 2.9-fold at 12.5 µM EA, p < 0.001) and protein (mean 7.1-fold at 12.5 µM EA, p = 0.002) in response to EA. SLPI mRNA also increased significantly (mean 1.4-fold at 25 µM EA, p = 0.01), but SLPI protein did not. Secretion of IL-2 but not of other cytokines/chemokines was induced by EA in a dose-dependent manner. EA was not cytotoxic. At the pre-attachment step, EA at CC20 and CC50 showed a slight trend towards inhibiting HPV16 pseudovirus, but this was not significant. In summary, vaginal epithelial cells can respond to EA by producing innate immune factors, and at tested concentrations, EA is not cytotoxic. Thus, plant-derived EA could be useful as an immunomodulatory agent to improve vaginal health.