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Introduction: Skeletal muscle regeneration is impaired in elderly. An oxidative stress-induced decrease in differentiation capacity of muscle satellite cells is a key factor in this process. The aim of this study is to investigate whether orange polyphenol hesperetin and pomegranate polyphenol ellagic acid enhance myoblast differentiation in the presence and absence of oxidative stress, and to explore underlying mechanisms. Methods: C2C12 myoblasts were proliferated for 24 h and differentiated for 120 h while exposed to hesperetin (5, 20, 50 µM), ellagic acid (0.05, 0.1 µM) or a combination (20 µM hesperetin, 0.05 µM ellagic acid) with and without oxidative stress-inducing compound menadione (9 µM) during 24 h of proliferation and during the first 5 h of differentiation. The number of proliferating cells was assessed using fluorescent labeling of incorporated 5-ethynyl-2'-deoxyuridine. Myosin heavy chain expression was assessed by fluorescence microscopy and cell fusion index was calculated. Furthermore, protein expression of phosphorylated p38 and myomixer were assessed using Western blot. Results: None of the compounds induced effects on cell proliferation. Without menadione, 50 µM hesperetin increased fusion index by 12.6% compared to control (p < 0.01), while ellagic acid did not affect measured parameters of differentiation. Menadione treatment did not change myosin heavy chain expression and fusion index. In combination with menadione, 20 µM hesperetin increased myosin heavy chain expression by 35% (p < 0.01) and fusion index by 7% (p = 0.04) compared to menadione. Furthermore, the combination of menadione with hesperetin and ellagic acid increased myosin heavy chain expression by 35% compared to menadione (p = 0.02). Hesperetin and ellagic acid did not change p38 phosphorylation and myomixer expression compared to control, while treatment with menadione increased p38 phosphorylation (p < 0.01) after 5 h and decreased myomixer expression (p = 0.04) after 72 h of differentiation. Conclusion and discussion: Hesperetin increased myosin heavy chain expression in the presence of oxidative stress induced by menadione, and increased cell fusion both in the presence and absence of menadione. Ellagic acid did not affect the measured parameters of myoblast differentiation. Therefore, hesperetin should be considered as nutritional prevention or treatment strategy to maintain muscle function in age-related diseases such as sarcopenia. Future research should focus on underlying mechanisms and translation of these results to clinical practice.

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The increase of oxidative stress level is one of the vital mechanisms of liver toxicity induced by arsenic (As). Ellagic acid (EA) is widely known due to its excellent antioxidation. Nevertheless, whether EA could alleviate As-induced oxidative stress and the underlying mechanisms remain unknown. Herein, As (2 and 4 µM) and EA (25 and 50 µM) were selected for alone and combined exposure of HepG2 cells to investigate the effects of EA on As-induced oxidative stress. Results indicated that EA could alleviate the oxidative stress caused by As via decreasing intracellular ROS level and MDA content, as well as improving SOD, CAT and GSH-PX activities. qRT-PCR showed that EA might enhance the expression levels of antioxidant enzymes NQO1, CAT and GPX1 by activating MAPK (JNK, p38 and ERK)/keap1-Nrf2 signaling pathway. EA was found to promote dissociation from keap1 and nuclear translocation of Nrf2 by competing with Nrf2 at ARG-380 and ARG-415 sites on keap1 to exert antioxidation using molecular docking. Moreover, metabolomics revealed that EA might maintain the redox balance of HepG2 cells by modulating or reversing disorders of carbon, amino acid, lipid and other metabolisms caused by As. This study provides diversified new insights for the removal of liver toxicity of As and the application of EA.

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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/ß-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.

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The spread of microbial resistance is a threat to public health. In this study, the anti-microbial, anti-biofilm, and efflux pump inhibitory effects of ellagic acid-loaded magnetic nanoparticles (Fe3O4NPs@EA) against beta-lactamase producing Escherichia coli isolates have been investigated. The effects of Fe3O4 NPs@EA on the growth inhibition of E. coli isolates were determined by disc diffusion method and determining the minimum inhibitory concentration was done using broth micro-dilution method. The anti-biofilm effect of nanoparticles was investigated using the microplate method. The efflux pump inhibitory effect of nanoparticles was investigated using cart-wheel method and by investigating the effect of nanoparticles on acrB and tolC genes expression levels. Fe3O4 NPs@EA showed anti-bacterial effects against test bacteria, and the MIC of these nanoparticles varied from 0.19 to 1.56 mg/mL. These nanoparticles caused a 43-62% reduction in biofilm formation of test bacteria compared to control. Furthermore, efflux pump inhibitory effect of these nanoparticles was confirmed at a concentration of 1/8 MIC, and the expression of acrB and tolC genes decreased in bacteria treated with 1/4 MIC Fe3O4 NPs@EA. According to the results, the use of nanoparticles containing ellagic acid can provide a basis for the development of new treatments against drug-resistant E. coli. This substance may improve the concentration of antibiotics in the bacterial cell and increase their effectiveness by inhibiting the efflux in E. coli isolates.

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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.

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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.

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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.

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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.

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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-1ß(IL-1ß), 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-1ß, 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-1ß, 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-1ß, 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-1ß, 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-1ß, 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.

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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.

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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.

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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.

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Objective: There is escalating evidence suggesting the beneficial effects of ellagic acid (EA) on the cardiovascular system. The aim of the present study was to investigate the protective effect of EA in human umbilical vein endothelial cells (HUVECs) against high glucose (HG)- induced endothelial dysfunction and to study the potential roles of adropin and nitric oxide (NO) in this regard. Materials and Methods: The experimental groups consisted of normal and HG (30 mM, 48 hr)-treated HUVECs incubated without or with 5 or 10 µM of EA (6 groups of at least 6 replicates, each). The cell count and viability were studied. Moreover, the markers of the redox state, including malondialdehyde (MDA), the activities of superoxide dismutase (SOD) and catalase enzymes, and ferric reducing anti-oxidant power (FRAP), were assayed. The levels of adropin and eNOS gene expression were also studied using RT-qPCR. Results: A high concentration of glucose reduced cell count and caused lipid peroxidation, reduced anti-oxidant capacity of the cells, decreased NO levels, and downregulated the expression of NOS3 (encoding eNOS) and ENHO (encoding adropin) genes. Ellagic acid reversed all these effects. Conclusion: These results suggest a significant protective effect for EA against HG-induced injury in HUVECs. The improved redox state and upregulation of NOS3 and ENHO genes seem to play critical roles in this regard.

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Introduction: Emergence of drug resistant strains of Plasmodium species has necessitated the search for novel antimalarials with unique mechanisms of action. Synthesis of hybrid compounds has been one approach to tackling this challenge. In this study, the synthesis of artesunate-ellagic acid hybrid compound (EA31) from ellagic acid and artesunate and its evaluation for antimalarial and antioxidant activities using in vitro and in vivo models were carried out. Method: EA31 was synthesized from artesunate and ellagic acid. The activities of the hybrid compound against Plasmodium falciparum W2 and P. berghei NK65 were evaluated, and its antioxidant activities were also determined. Results: The results revealed that EA31 was more active against P. falciparum W2 (chloroquine resistant) clone and less cytotoxic to buffalo green monkey kidney cell line compared to artesunate. EA31 was also active against Plasmodium berghei NK65 in vivo. The results revealed inhibition of ß-hematin formation as one of the mechanisms of action of EA31. EA31 also exhibited antioxidant activities. Conclusion: The results revealed that EA31 may exert dual action of killing malaria parasite and mopping the reactive oxygen species that mediate the secondary complications of malaria.

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Heat stress has been shown to have a detrimental impact on testicular activity and spermatogenesis. Ellagic acid is a plant-derived organic compound that has a variety of biological functions. Thus, it is believed that ellagic acid may improve heat-stressed testicular dysfunction. There has been no research on the impact of ellagic acid on heat-stressed testicular dysfunction. The mice were divided into 4 groups. The first group was the normal control group (CN), and the second received heat stress (HS) by submerging the lower body for 15 min in a water bath with a thermostatically controlled temperature kept at 43°C (HS), and the third and fourth groups were subjected to heat-stress similar to group two and given two different dosages of ellagic acid (5 mg/kg (EH5) and 50 mg/kg (EH50) for 14 days. Ellagic acid at a dose of 50 mg/kg improved the level of circulating testosterone (increased 3ßHSD) and decreases the oxidative stress. The testicular and epididymal architecture along with sperm parameters also showed improvement. Ellagic acid treatment significantly increases the germ cell proliferation (GCNA, BrdU staining) and Bcl2 expression and decreases active caspase 3 expression. Heat stress downregulated the expression of AR, ER-α and ER-ß, and treatment with ellagic acid increased the expression of ER-α and ER-ß markers in the 50 mg/kg treatment group. Thus, our finding suggests that ellagic acid ameliorates heat-induced testicular impairment through modulating testosterone synthesis, germ cell proliferation, and oxidative stress. These effects could be manifested by regulating androgen and estrogen receptors. However, the two doses showed differential effects of some parameters, which require further investigation.

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Phyllanthus emblica (P. emblica) is a vital medicinal plant with both medical and edible values. In the quality standard of P. emblica listed by the Chinese Pharmacopoeia, gallic acid is used as the index component for the content determination. However, a large number of tannin components can be decomposed into gallic acid during its refluxing extraction process, thus affecting the accuracy and specificity of the content determination. Thus, the index component used for the quality control needs to be further determined. In this study, the quality markers of P. emblica was specified by integrating chromatographic fingerprint, serum pharmacochemistry and network pharmacology. The chromatographic fingerprint of 18 batches of P. emblica samples were established by ultra-high-performance liquid chromatography (UPLC), and 8 differential components causing quality fluctuation were identified by chemometric analysis and UPLC-Q-TOF/MS analysis. Afterwards, 14 prototype migration components absorbed into the blood after gavage administration to rats were identified by UPLC-Q-TOF/MS analysis. Subsequently, a network pharmacology approach was used to construct the component-target-disease-pathway network, resulting in the identification of 22 components responsible for efficacy of P. emblica. Finally, by integrating the above results, ellagic acid was screened out as one of the Q-markers and could be employed as a quantitative component of P. emblica to improve the quality standard. The strategy is also informative for discovering Q-markers of other TCMs.

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Diabetes mellitus (DM) is a worldwide-concerning disease with a rising prevalence. There are many ongoing studies aimed at finding new and effective treatments. Ellagic acid (EA) is a natural polyphenolic compound abundant in certain fruits and vegetables. It is the objective of this investigation to assess the effectiveness and preventive mechanisms of EA on DM and associated complications. This systematic review used PubMed, Scopus, and Google Scholar as search databases using a predetermined protocol from inception to June 2024. We assessed all related English studies, including in vitro, in vivo, and clinical trials. EA counteracted DM and its complications by diminishing inflammation, oxidative stress, hyperglycemia, apoptosis, insulin resistance, obesity, lipid profile, and histopathological alterations. Several mechanisms contributed to the anti-diabetic effect of EA, the most significant being the upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), peroxisome proliferator-activated receptor gamma (PPAR-γ), protein kinase B, and downregulation of nuclear factor-kappa-B (NF-κB) gene expression. EA also revealed protective effects against diabetes complications, such as diabetic-induced hepatic damage, testicular damage, endothelial dysfunction, muscle dysfunction, retinopathy, nephropathy, cardiomyopathy, neuropathy, and behavioral deficit. Administration of EA could have various protective effects in preventing, treating, and alleviating DM and its complications. Although it could be considered a cost-effective, safe, and accessible treatment, to fully establish the effectiveness of EA as a medication for DM, it is crucial to conduct further well-designed studies.

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Specific anthocyanins and phenolic compounds exhibit acetylcholinesterase inhibitory (AChEi) activity. In this study, the AChEi activity of jaboticaba peel extracts were investigated based on their high phenol contents. Jaboticaba peel ethanolic extract (PEX) and aqueous extract (PAX) were prepared by extracting jaboticaba peel with 95% ethanol and boiling water, respectively. Through HPLC-MS/MS and HPLC-PDA analysis, gallic acid was identified in PAX with a concentration of 598.13 ± 42.43 mg/100 g extract, and ellagic acid in PEX with a concentration of 350.47 ± 8.53 mg/100 g extract. Both PEX and PAX showed dose-dependent inhibition against AChE activity, with IC50 values of 3.54 and 4.07 mg/mL, respectively. The mechanism of inhibition of PEX was determined to be non-competitive inhibition based on the decreasing V max and relatively constant K m with increasing PEX concentration, as determined using a Lineweaver-Burk plot.

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The aim of this work was to develop and characterize a thin films composed of hyaluronic acid/ellagic acid for potential medical application. Its principal novelty, distinct from the prior literature in terms of hyaluronic acid films supplemented with phenolic acids, resides in the predominant incorporation of ellagic acid-a distinguished compound-as the primary constituent of the films. Herein, ellagic acid was dissolved in two different solvents, i.e., acetic acid (AcOH) or sodium hydroxide (NaOH), and the surface properties of the resultant films were assessed using atomic force microscopy and contact angle measurements. Additionally, various physicochemical parameters were evaluated including moisture content, antioxidant activity, and release of ellagic acid in phosphate buffered saline. Furthermore, the evaluation of films' biocompatibility was conducted using human epidermal keratinocytes, dermal fibroblasts, and human amelanotic melanoma cells (A375 and G361), and the antimicrobial activity was elucidated accordingly against Staphylococcus aureus ATCC 6538 and Pseudomonas aeruginosa ATCC 15442. Our results showed that the films exhibited prominent antibacterial properties particularly against Staphylococcus aureus, with the 80HA/20EA/AcOH film indicating the strong biocidal activity against this strain leading to a significant reduction in viable cells. Comparatively, the 50HA/50EA/AcOH film also displayed biocidal activity against Staphylococcus aureus. This experimental approach could be a promising technique for future applications in regenerative dermatology or novel strategies in terms of bioengineering.

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The pomegranate processing industry generates worldwide enormous amounts of by-products, such as pomegranate peels (PPs), which constitute a rich source of phenolic compounds. In this view, PPs could be exploited as a sustainable source of ellagic acid, which is a compound that possesses various biological actions. The present study aimed at the liberation of ellagic acid from its bound forms via ultrasound-assisted alkaline hydrolysis, which was optimized using response surface methodology. The effects of duration of sonication, solvent:solid ratio, and NaOH concentration on total phenol content (TPC), antioxidant activity, and punicalagin and ellagic acid content were investigated. Using the optimum hydrolysis conditions (i.e., 32 min, 1:48 v/w, 1.5 mol/L NaOH), the experimental responses were found to be TCP: 4230 ± 190 mg GAE/100 g dry PPs; AABTS: 32,398 ± 1817 µmol Trolox/100 g dry PPs; ACUPRAC: 29,816 ± 1955 µmol Trolox/100 g dry PPs; 59 ± 3 mg punicalagin/100 g dry PPs; and 1457 ± 71 mg ellagic acid/100 g dry PPs. LC-QTOF-MS and GC-MS analysis of the obtained PP extract revealed the presence of various phenolic compounds (e.g., ellagic acid), organic acids (e.g., citric acid), sugars (e.g., fructose) and amino acids (e.g., glycine). The proposed methodology could be of use for food, pharmaceutical, and cosmetics applications, thus reinforcing local economies.

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