-
Molecular Nutrition & Food Research Oct 2020This work aims at evaluating the effect of dietary ellagic acid (EA) and its microbial metabolite urolithin A (UA) on glucose metabolism and insulin resistance (IR) in...
SCOPE
This work aims at evaluating the effect of dietary ellagic acid (EA) and its microbial metabolite urolithin A (UA) on glucose metabolism and insulin resistance (IR) in mice with diet-induced IR.
METHODS AND RESULTS
DBA2J mice are fed a high fat/high sucrose diet (HF/HS) for 8 weeks to induce IR and then 0.1% EA, UA, or EA and UA (EA+UA) are added to the HF/HS-diet for another 8 weeks. UA significantly decreases fasting glucose and increases adiponectin compared with HF/HS-controls. During intraperitoneal insulin tolerance test, EA+UA significantly improve insulin-mediated glucose lowering effects at 15 and 120 min and reduce blood triglycerides compared with HF/HS-controls. Serum free fatty acids are significantly decreased by EA, UA, and EA+UA. Differential expression of genes related to mitochondrial function by EA, UA, and EA+UA in liver and skeletal muscle is observed. Primary hepatocytes from IR-mice have higher proton leak, basal and ATP-linked oxygen consumption rates compared with healthy controls. EA and EA+UA but not UA reduce the proton leak in hepatocytes from IR-mice.
CONCLUSION
EA and UA induce different metabolic benefits in IR mice. The effects of EA and UA on mitochondrial function suggest a potentially novel mechanism modulating metabolism.
Topics: Adiponectin; Animals; Blood Glucose; Coumarins; Cytokines; Diet, High-Fat; Ellagic Acid; Gene Expression; Inflammation; Insulin Resistance; Lipid Metabolism; Lipids; Liver; Male; Mice, Inbred DBA; Mitochondria, Liver; Muscle, Skeletal; Sucrose
PubMed: 32783299
DOI: 10.1002/mnfr.202000091 -
Journal of Pharmacological Sciences May 2020Valproic acid is a commonly used drug for many psychiatric disorders, particularly for epilepsy. However, it has been reported that its use is associated with possible...
Valproic acid is a commonly used drug for many psychiatric disorders, particularly for epilepsy. However, it has been reported that its use is associated with possible side effects including hepatotoxicity. The present study investigated the hepatoprotective effect of ellagic acid against valproic acid-induced hepatotoxicity in rats. Ellagic acid (60 mg/kg/day; p.o) was treated for one week, followed by concomitant injection of valproic acid (250 mg/kg/day; i.p.) for another 14 consecutive days to induce hepatocellular damage in adult Sprague-Dawley rats. Valproic acid showed a marked increase in serum enzyme activities, AST, ALT, ALP and GGT. In addition, it significantly increased MDA and NO along with a marked decline in reduced GSH content. At the same time, valproic acid administration resulted in marked elevation in hydroxyproline, TNF-α production and NF-kB expression. These results were confirmed by histopathological examination. Treatment with ellagic acid markedly attenuated valproic acid-induced hepatic injury in rats.
Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Ellagic Acid; Glutathione; Liver; Male; Nitric Oxide; Oxidative Stress; Phytotherapy; Rats, Sprague-Dawley; Valproic Acid
PubMed: 32139333
DOI: 10.1016/j.jphs.2020.01.007 -
Cells Feb 2021Multidrug resistance (MDR) is one of the major clinical challenges in cancer treatment and compromises the effectiveness of conventional anticancer chemotherapeutics.... (Review)
Review
Multidrug resistance (MDR) is one of the major clinical challenges in cancer treatment and compromises the effectiveness of conventional anticancer chemotherapeutics. Among known mechanisms of drug resistance, drug efflux via ATP binding cassette (ABC) transporters, namely P-glycoprotein (P-gp) has been characterized as a major mechanism of MDR. The primary function of ABC transporters is to regulate the transport of endogenous and exogenous small molecules across the membrane barrier in various tissues. P-gp and similar efflux pumps are associated with MDR because of their overexpression in many cancer types. One of the intensively studied approaches to overcome this mode of MDR involves development of small molecules to modulate P-gp activity. This strategy improves the sensitivity of cancer cells to anticancer drugs that are otherwise ineffective. Although multiple generations of P-gp inhibitors have been identified to date, reported compounds have demonstrated low clinical efficacy and adverse effects. More recently, natural polyphenols have emerged as a promising class of compounds to address P-gp linked MDR. This review highlights the chemical structure and anticancer activities of selected members of a structurally unique class of 'biaryl' polyphenols. The discussion focuses on the anticancer properties of ellagic acid, ellagic acid derivatives, and schisandrins. Research reports regarding their inherent anticancer activities and their ability to sensitize MDR cell lines towards conventional anticancer drugs are highlighted here. Additionally, a brief discussion about the axial chirality (i.e., atropisomerism) that may be introduced into these natural products for medicinal chemistry studies is also provided.
Topics: Animals; Cyclooctanes; Drug Discovery; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Ellagic Acid; Humans; Lignans; Neoplasms; Polycyclic Compounds; Polyphenols
PubMed: 33669953
DOI: 10.3390/cells10020458 -
Journal of Cellular and Molecular... Dec 2023Ellagic acid (EA) is a natural polyphenolic compound. Recent studies have shown that EA has potential anticancer properties against gastric cancer (GC). This study aims...
Ellagic acid (EA) is a natural polyphenolic compound. Recent studies have shown that EA has potential anticancer properties against gastric cancer (GC). This study aims to reveal the potential targets and mechanisms of EA against GC. This study adopted methods of bioinformatics analysis and network pharmacology, including the weighted gene co-expression network analysis (WGCNA), construction of protein-protein interaction (PPI) network, receiver operating characteristic (ROC) and Kaplan-Meier (KM) survival curve analysis, Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, molecular docking and molecular dynamics simulations (MDS). A total of 540 EA targets were obtained. Through WGCNA, we obtained a total of 2914 GC clinical module genes, combined with the disease database for screening, a total of 606 GC-related targets and 79 intersection targets of EA and GC were obtained by constructing Venn diagram. PPI network was constructed to identify 14 core candidate targets; TP53, JUN, CASP3, HSP90AA1, VEGFA, HRAS, CDH1, MAPK3, CDKN1A, SRC, CYCS, BCL2L1 and CDK4 were identified as the key targets of EA regulation of GC by ROC and KM curve analysis. The enrichment analysis of GO and KEGG pathways of key targets was performed, and they were mainly enriched in p53 signalling pathway, PI3K-Akt signalling pathway. The results of molecular docking and MDS showed that EA could effectively bind to 13 key targets to form stable protein-ligand complexes. This study revealed the key targets and molecular mechanisms of EA against GC and provided a theoretical basis for further study of the pharmacological mechanism of EA against GC.
Topics: Humans; Ellagic Acid; Network Pharmacology; Stomach Neoplasms; Molecular Docking Simulation; Phosphatidylinositol 3-Kinases; Computational Biology; Drugs, Chinese Herbal
PubMed: 37794689
DOI: 10.1111/jcmm.17967 -
BMC Complementary Medicine and Therapies Mar 2023Aging is associated with impaired renal function and structural alterations. Oxidative stress plays a vital role in renal senescence and damage. Sirtuin 1 (SIRT1) is...
BACKGROUND
Aging is associated with impaired renal function and structural alterations. Oxidative stress plays a vital role in renal senescence and damage. Sirtuin 1 (SIRT1) is thought to protect cells from oxidative stress through nuclear factor erythroid 2-related factor 2 (NRF2). Ellagic acid (EA), a natural antioxidant, has been demonstrated to have renoprotective roles in vitro and in vivo. This study investigated if SIRT1 and NRF2 mediate the protective effects of EA in aged kidneys.
METHODS
Male Wistar rats were divided into three groups including young (4 months), old, and old + EA (25 months). Young and old groups received EA solvent, while the old + EA group was treated with EA (30 mg/kg) by gavage for 30 days. Then, the level of renal oxidative stress, SIRT1 and NRF2 expression, kidney function parameters, and histopathological indices were measured.
RESULTS
Treatment with EA significantly increased the level of antioxidant enzymes and reduced malondialdehyde concentration (P < 0.01). Moreover, EA administration remarkably upregulated mRNA and protein levels of SIRT1 and NRF2 as well as deacetylated NRF2 protein (P < 0.05). Additionally, EA treated rats improved kidney function and histopathological scores (P < 0.05).
CONCLUSIONS
These findings suggest that ellagic acid exerts protective effects on aged kidneys by activating SIRT1 and NRF2 signaling.
Topics: Rats; Male; Animals; Antioxidants; Sirtuin 1; Ellagic Acid; NF-E2-Related Factor 2; Rats, Wistar; Oxidative Stress; Kidney; Aging
PubMed: 36899375
DOI: 10.1186/s12906-023-03907-y -
Oxidative Medicine and Cellular... 2020Oxidative stress is a state of excess of prooxidative species relative to the antioxidant defenses (enzymatic and nonenzymatic) in a living organism. The consequence of... (Review)
Review
Oxidative stress is a state of excess of prooxidative species relative to the antioxidant defenses (enzymatic and nonenzymatic) in a living organism. The consequence of this imbalance is damage of the major cellular macromolecules (carbohydrates, lipids, proteins, and DNA), which further leads to a gradual loss of tissue and organ function. It has been shown that oxidative stress plays an important role in the pathogenesis of many chronic diseases (cardiovascular, metabolic, and neurodegenerative diseases and cancer) and in the process of aging. Thus, many strategies to combat oxidative stress have been proposed and tested. In this context, food rich in antioxidants has received great attention. Pomegranate, berries, and walnuts have been recognized as "superfood" particularly for their cardioprotective effects. The common characteristic of these foods is the high content of ellagitannins. Since tannins are not bioavailable, they have been neglected in nutrition science and even considered antinutrients for a long time. However, this view has changed dramatically once it was recognized that ellagic acid, released from ellagitannins in the gastrointestinal system, is further metabolized by colonic microbiota to bioavailable compounds-known as urolithins. Thus, urolithins (3,4-benzocoumarin derivatives) have emerged as novel natural bioactive compounds and are now the focus of extensive investigations. So far, urolithins were shown to be powerful modulators of oxidative stress and agents with potential anti-inflammatory, antiproliferative, and antiaging properties. Furthermore, a few synthetic derivatives of urolithins were recognized as lead compounds for new drug development. Available data on urolithin synthesis, physicochemical and pharmacokinetic characteristics, biological activity, and safety will be presented in this review.
Topics: Coumarins; Ellagic Acid; Humans; Oxidative Stress
PubMed: 32774676
DOI: 10.1155/2020/5194508 -
Foods (Basel, Switzerland) Oct 2022Oil is extracted from walnut leaves behind large quantities of defatted press cake that is still rich in valuable nutrients. and , two molds traditionally used in Asia,...
Oil is extracted from walnut leaves behind large quantities of defatted press cake that is still rich in valuable nutrients. and , two molds traditionally used in Asia, have the necessary enzymes to use the nutrients in the walnut press cake. Walnuts and the press cake contain ellagitannins, known as precursors for ellagic acid and urolithins. In this study, experiments to optimize the solid-state fermentation of walnut press cake were performed in order to liberate ellagic acid from ellagitannins. Extracts of fermented products were then analyzed with an HPLC-DAD to measure the liberation of ellagic acid from ellagitannins. Good growth of and mycelia on the walnut press cake was observed. A single mold culture was subjected to a hydration of 0.8 mL/g, an addition of 37.5 mmol/kg acetic acid (AA) and 1% NaCl, and an incubation temperature of 25 °C; these were observed to be good conditions for solid-state fermentation for walnut press cake. The highest ellagic acid concentration was obtained at 48 h. At 72 h, degradation dominated the liberation of ellagic acid.
PubMed: 36230178
DOI: 10.3390/foods11193102 -
Journal of Advanced Pharmaceutical... 2021Calcium hydroxide induces chronic inflammation and pulp tissue necrosis due to its high pH value. Ellagic acid is an anti-inflammatory and antioxidant flavonoid....
Calcium hydroxide induces chronic inflammation and pulp tissue necrosis due to its high pH value. Ellagic acid is an anti-inflammatory and antioxidant flavonoid. Therefore, the effect of combining calcium hydroxide and ellagic acid must be researched to reduce cell damage due to the application of calcium hydroxide. The objective of the study was to determine the cytotoxicity and proliferation of fibroblasts after combining calcium hydroxide and ellagic acid with ratios of 99:1, 98:2, 97:3, 96:4, and 95:5. Calcium hydroxide and ellagic acid with different ratios were mixed with water and stirred. Rat gingival fibroblasts were prepared and incubated in two 96-well microplates. The control group and treatment groups (16 samples) were placed in the microplate and incubated for 1 and 3 days. An MTT assay test was performed, and the absorbance was observed using the ELISA reader with a wavelength of 540 nm. Following that, the cell viability was calculated. The results were tabulated and analyzed using a one-way ANOVA. For all treatment groups, the fibroblast cells showed a viability of higher than 50%. There was a significant increase ( < 0.05) in the fibroblast cell proliferation after combining calcium hydroxide and ellagic acid with ratios of 99:1 and 97:3. The combination of calcium hydroxide and ellagic acid is nontoxic. The treatment groups with ratios of 99:1 and 97:3 showed increased fibroblast cell proliferation.
PubMed: 33532351
DOI: 10.4103/japtr.JAPTR_154_20 -
Molecules (Basel, Switzerland) Sep 2022Ellagic acid is a natural polyphenol found in various fruits and vegetables. Numerous studies have shown that ellagic acid has beneficial effects on human health. In...
Ellagic acid is a natural polyphenol found in various fruits and vegetables. Numerous studies have shown that ellagic acid has beneficial effects on human health. In this study, we investigated the stress resistant action of ellagic acid in (). Notably, 50 μM ellagic acid prolonged the lifespan of by 36.25%, 36.22%, 155.1%, and 79.07% under ultraviolet radiation stress, heat stress, oxidative stress, and infection stress, respectively. Furthermore, the mechanism by which ellagic acid reduces the damage caused by ultraviolet radiation in was explored. Ellagic acid could significantly induce the nucleus translocation of DAF-16 and, thereby, activate a series of target genes to resist ultraviolet radiation stress. Moreover, ellagic acid also significantly increased the expression of SOD-3 by 3.61 times and the activity of superoxide dismutase by 3.70 times to clean out harmful reactive oxygen species in exposed to ultraviolet radiation stress. In both mutant and ; double-mutant worms exposed to ultraviolet radiation, ellagic acid could no longer prolong their lifespan. These results indicate that ellagic acid plays an important role in resisting ultraviolet radiation stress in probably in an insulin/IGF-1 signaling pathway-dependent way.
Topics: Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Ellagic Acid; Forkhead Transcription Factors; Humans; Insulin; Insulin-Like Growth Factor I; Longevity; Oxidative Stress; Polyphenols; Reactive Oxygen Species; Signal Transduction; Superoxide Dismutase; Ultraviolet Rays
PubMed: 36234702
DOI: 10.3390/molecules27196168 -
Nutrients Jul 2023Unripe (uRO) contains various natural polyphenols with beneficial physiological activities and is particularly rich in ellagic acid (EA). EA has ameliorated type 2...
Unripe (uRO) contains various natural polyphenols with beneficial physiological activities and is particularly rich in ellagic acid (EA). EA has ameliorated type 2 inflammation and airway hyperresponsiveness in animal models of eosinophilic asthma. EA is metabolized by the gut microbiota to urolithin A (UA), which exhibits anti-inflammatory properties. However, it remains unclear whether uRO, EA, and UA reduce inflammatory responses and oxidative stress in respiratory epithelial cells and neutrophils. In this study, inflammation was induced in A549 (human lung epithelial cells) and dHL-60 cells (neutrophil-like cells differentiated from human promyelocytic leukemia HL-60 cells) and treated with various concentrations of water extract of uRO (uRO-w), EA, and UA. EA, uRO-w and UA suppressed the inflammatory cytokine and chemokine levels and reduced the expression of matrix metalloproteinase-9 in A549 cells stimulated with IL-1β. As a result of analyzing the mechanism by which these inflammatory molecules are expressed, it was found that EA, uRO-w, and UA regulated corticosteroid-sensitive mitogen activated protein kinase, nuclear factor κB, and corticosteroid-insensitive AKT. In addition, uRO-w, EA, and UA significantly reduced reactive oxygen species levels in phorbol 12-myristate 13-acetate-stimulated dHL-60 cells and inhibited neutrophil extracellular trap formation. Therefore, our results suggest that uRO-w, EA, and UA are potential therapeutic agents for preventing and treating inflammatory respiratory diseases.
Topics: Animals; Humans; HL-60 Cells; Ellagic Acid; Rubus; A549 Cells; Inflammation
PubMed: 37571300
DOI: 10.3390/nu15153364