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Oxidative Medicine and Cellular... 2022Ellagic acid (EA) is a bioactive polyphenolic compound naturally occurring as secondary metabolite in many plant taxa. EA content is considerable in pomegranate ( L.)... (Review)
Review
Ellagic acid (EA) is a bioactive polyphenolic compound naturally occurring as secondary metabolite in many plant taxa. EA content is considerable in pomegranate ( L.) and in wood and bark of some tree species. Structurally, EA is a dilactone of hexahydroxydiphenic acid (HHDP), a dimeric gallic acid derivative, produced mainly by hydrolysis of ellagitannins, a widely distributed group of secondary metabolites. EA is attracting attention due to its antioxidant, anti-inflammatory, antimutagenic, and antiproliferative properties. EA displayed pharmacological effects in various and model systems. Furthermore, EA has also been well documented for its antiallergic, antiatherosclerotic, cardioprotective, hepatoprotective, nephroprotective, and neuroprotective properties. This review reports on the health-promoting effects of EA, along with possible mechanisms of its action in maintaining the health status, by summarizing the literature related to the therapeutic potential of this polyphenolic in the treatment of several human diseases.
Topics: Animals; Anti-Allergic Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Ellagic Acid; Fruit; Gastrointestinal Tract; Humans; Hydrolyzable Tannins; Hypoglycemic Agents; Phytotherapy; Plant Extracts; Plants; Polyphenols; Protective Agents
PubMed: 35237379
DOI: 10.1155/2022/3848084 -
Cell Death & Disease Jun 2022Benign prostate hyperplasia (BPH) is an age-related disease in men characterized by the growth of prostate cells and hyperproliferation of prostate tissue. This...
Benign prostate hyperplasia (BPH) is an age-related disease in men characterized by the growth of prostate cells and hyperproliferation of prostate tissue. This condition is closely related to chronic inflammation. In this study, we highlight the therapeutic efficacy of ellagic acid (EA) for BPH by focusing on the AR signaling axis and STAT3. To investigate the effect of EA on BPH, we used EA, a phytochemical abundant in fruits and vegetables, to treat testosterone propionate (TP)-induced BPH rats and RWPE-1 human prostate epithelial cells. The EA treatment reduced prostate weight, prostate epithelial thickness, and serum DHT levels in the TP-induced BPH rat model. In addition, EA improved testicular injury by increasing antioxidant enzymes in testis of the BPH rats. EA reduced the protein levels of AR, 5AR2, and PSA. It also induced apoptosis by regulating Bax, Bcl_xL, cytochrome c, caspase 9, and caspase 3 with increasing mitochondrial dynamics. Furthermore, EA reduced the expression of IL-6, TNF-α, and NF-κB, as well as phosphorylation of STAT3 and IκBα. These findings were also confirmed in TP-treated RWPE-1 cells. Overall, our data provide evidence of the role of EA in improving BPH through inhibition of AR and the STAT3 pathway.
Topics: Androgens; Animals; Ellagic Acid; Humans; Hyperplasia; Male; Plant Extracts; Prostate; Prostatic Hyperplasia; Rats; Rats, Sprague-Dawley; STAT3 Transcription Factor; Testosterone Propionate
PubMed: 35715415
DOI: 10.1038/s41419-022-04995-3 -
Biomedicine & Pharmacotherapy =... Feb 2019As a promising new target, miR-233 may regulate oxidative stress by targeting keap1-Nrf2 system to affect the pathological process of liver injury in T2DM. Ellagic acid...
As a promising new target, miR-233 may regulate oxidative stress by targeting keap1-Nrf2 system to affect the pathological process of liver injury in T2DM. Ellagic acid (EA) is versatile for protecting oxidative stress damage and metabolic disorders. In the present study, we investigated the effect of EA on oxidative stress and insulin resistance in high glucose-induced T2DM HepG2 cells and examined the role of miR-223/keap1-Nrf2 pathway in system. HepG2 cells were incubated in 30 mM of glucose, with or without EA (15 and 30 μM) or metformin (Met, 150 μM) for 12 h. Glucose consumption, phosphorylation of IRS1, Akt and ERK under insulin stimulation, ROS and O production, MDA level, SOD activity and miR-223 expression, as well as protein levels of keap1, Nrf2, HO-1, SOD1 and SOD2 were analyzed. Furthermore, dual luciferase reporter assay, miR-223 mimic and inhibitor were implemented in cellular studies to explore the possible mechanism. EA upregulated glucose consumption, IRS1, Akt and ERK phosphorylation under insulin stimulation, reduced ROS and O production and MDA level, and increased SOD activity in high glucose-exposed HepG2 cells. In addition, EA elevated miR-223 expression level, downregulated mRNA and protein levels of keap1, and upregulated Nrf2, HO-1, SOD1 and SOD2 protein levels in this cell model. What's more, dual luciferase reporter assay, miR-223 mimic and inhibitor transfection confirmed that EA activated keap1-Nrf2 system via elevating miR-223. The miR-223, a negative regulator of keap1, represents an attractive therapeutic target in hepatic injury in T2DM. EA ameliorates oxidative stress and insulin resistance via miR-223-mediated keap1-Nrf2 activation in high glucose-induced T2DM HepG2 cells.
Topics: Cell Survival; Dose-Response Relationship, Drug; Ellagic Acid; Glucose; Hep G2 Cells; Humans; Insulin Resistance; Kelch-Like ECH-Associated Protein 1; MicroRNAs; NF-E2-Related Factor 2; Oxidative Stress; Reactive Oxygen Species; Signal Transduction
PubMed: 30466006
DOI: 10.1016/j.biopha.2018.11.018 -
Molecular Nutrition & Food Research Nov 2022Urolithins, metabolites produced by the gut microbiota from the polyphenols ellagitannins and ellagic acid, are discovered by the research group in humans almost 20... (Review)
Review
Urolithins, metabolites produced by the gut microbiota from the polyphenols ellagitannins and ellagic acid, are discovered by the research group in humans almost 20 years ago. Pioneering research suggests urolithins as pleiotropic bioactive contributors to explain the health benefits after consuming ellagitannin-rich sources (pomegranates, walnuts, strawberries, etc.). Here, this study comprehensively updates the knowledge on urolithins, emphasizing the review of the literature published during the last 5 years. To date, 13 urolithins and their corresponding conjugated metabolites (glucuronides, sulfates, etc.) have been described and, depending on the urolithin, detected in different human fluids and tissues (urine, blood, feces, breastmilk, prostate, colon, and breast tissues). There has been a substantial advance in the research on microorganisms involved in urolithin production, along with the compositional and functional characterization of the gut microbiota associated with urolithins metabolism that gives rise to the so-called urolithin metabotypes (UM-A, UM-B, and UM-0), relevant in human health. The design of in vitro studies using physiologically relevant assay conditions (molecular forms and concentrations) is still a pending subject, making some reported urolithin activities questionable. In contrast, remarkable progress has been made in the research on the safety, bioactivity, and associated mechanisms of urolithin A, including the first human interventions.
Topics: Male; Humans; Gastrointestinal Microbiome; Coumarins; Hydrolyzable Tannins; Feces; Ellagic Acid; Juglans
PubMed: 35118817
DOI: 10.1002/mnfr.202101019 -
Redox Biology Oct 2022Chronic liver injury causing liver fibrosis is a major cause of morbidity and mortality worldwide. Targeting the suppression of hepatic stellate cell (HSC) activation is...
Chronic liver injury causing liver fibrosis is a major cause of morbidity and mortality worldwide. Targeting the suppression of hepatic stellate cell (HSC) activation is recognized as an effective strategy for the treatment of liver fibrosis. Ellagic acid (EA), a natural polyphenol product isolated from fruits and vegetables, possesses many biological functions. Here, EA exerts its antifibrotic activity by inducing ferroptotic cell death of activated HSCs, which is accompanied by redox-active iron accumulation, lipid peroxidation, and GSH depletion in CCl mice and human LX-2 cells. The specific ferroptosis inhibitor ferrostatin-1 prevented EA-induced ferroptotic cell death. Mechanistically, EA impairs the formation of vesicle-associated membrane protein 2 (VAMP2)/syntaxin 4 and VAMP2/synaptosome-associated protein 23 complexes by suppressing VAMP2 expression by enhancing its degradation in a proteasome-dependent pathway. This leads to the impairment of ferroportin (FPN, an iron exporter) translocation and intracellular iron extrusion. Interestingly, VAMP2 overexpression inhibits the role of EA in blocking FPN translocation and increasing intracellular ferritin content (an iron storage marker). In contrast, VAMP2 knockdown shows a synergistic effect on EA-mediated ferroptotic events in both HSCs. Additionally, HSC-specific overexpression of VAMP2 impaired EA-induced HSC ferroptosis in mouse liver fibrosis, and HSC-specific VAMP2 knockdown increased the inhibitory effect of EA on fibrosis. Taken together, our data suggest that the natural product EA exerts its antifibrotic effects by inducing FPN-dependent ferroptosis of HSCs by disrupting the formation of SNARE complexes, and EA will hopefully serve as a prospective compound for liver fibrosis treatment.
Topics: Animals; Biological Products; Cation Transport Proteins; Ellagic Acid; Ferritins; Ferroptosis; Hepatic Stellate Cells; Humans; Iron; Liver Cirrhosis; Mice; Polyphenols; Prospective Studies; Proteasome Endopeptidase Complex; Qa-SNARE Proteins; Signal Transduction; Vesicle-Associated Membrane Protein 2
PubMed: 36029649
DOI: 10.1016/j.redox.2022.102435 -
Drug Discoveries & Therapeutics Jul 2022There are trillions of microorganisms in the human intestine. They can react to the intestinal microenvironment by metabolizing food or producing small molecular... (Review)
Review
There are trillions of microorganisms in the human intestine. They can react to the intestinal microenvironment by metabolizing food or producing small molecular compounds to affect the host's digestive ability and resist the risk of infection and autoimmune diseases. Many studies have revealed that intestinal flora and its metabolites play an important role in human physiology and the development of diseases. Urolithins are kind of intestinal microbiota metabolites of ellagitannins (ETs) and ellagic acid (EA) with potent biological activity in vivo. However, different individuals have different intestinal flora. According to the different metabolites from ETs and EA, it is divided into three metabo-types including UM-A, UM-B and UM-0. This paper reviews the origin of urolithins, the urolithin producing microorganisms and the effects of urolithins on regulating intestinal diseases. This review will provide a theoretical basis for the regulation of urolithins in the homeostasis of intestinal flora and a reference for the scientific utilization of urolithins and foods rich in ETs and EA.
Topics: Coumarins; Ellagic Acid; Gastrointestinal Microbiome; Humans; Hydrolyzable Tannins; Intestines
PubMed: 35753772
DOI: 10.5582/ddt.2022.01039 -
International Journal of Molecular... Sep 2022Aging is an unavoidable biological process that leads to the decline of human function and the reduction in people's quality of life. Demand for anti-aging medicines has... (Review)
Review
Aging is an unavoidable biological process that leads to the decline of human function and the reduction in people's quality of life. Demand for anti-aging medicines has become very urgent. Many studies have shown that ellagic acid (EA), a phenolic compound widely distributed in dicotyledonous plants, has powerful anti-inflammation and antioxidant properties. Moreover, it has been demonstrated that EA can enhance neuronal viability, reduce neuronal defects, and alleviate damage in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and cerebral ischemia. This paper reviews the biochemical functions and neuroprotective effects of EA, showing the clinical value of its application.
Topics: Aging; Antioxidants; Central Nervous System; Ellagic Acid; Humans; Neuroprotective Agents; Quality of Life
PubMed: 36142849
DOI: 10.3390/ijms231810937 -
Journal of Oral Biology and... 2022The combination of hydroxyapatite and the herbal extract ellagic acid is expected to accelerate the bone healing process (osteogenesis) due to the extract's...
The combination of hydroxyapatite and the herbal extract ellagic acid is expected to accelerate the bone healing process (osteogenesis) due to the extract's anti-inflammatory and antioxidant properties. The osteogenesis process is closely associated with angiogenesis markers, such as fibroblast growth factor 2 (FGF-2), vascular endothelial growth factor (VEGF) and alkali phosphatase (ALP). The objective of this study is to analyse the combination of ellagic acid and hydroxyapatite to promote FGF-2, VEGF and ALP expression as angiogenesis markers in a bone defect model. The research sample comprised 30 male Wistar rats with a defect introduced on the left femur; these were divided into three groups for treatment with ellagic acid and hydroxyapatite, hydroxyapatite and polyethylene glycol (PEG) (control). On days 7 and 14 days after treatment, the Wistar rats were euthanised, and the femoral bone tissue was removed for the immunohistochemical analysis of FGF-2, VEGF and ALP expression. FGF-2 and ALP expression increased in the group treated with ellagic acid and hydroxyapatite on days 7 and 14 post treatment (p < 0.05), and there was an increase in VEGF expression on day 7 post treatment (p < 0.05). The combination of ellagic acid and hydroxyapatite promoted FGF-2, VEGF and ALP expression as angiogenesis markers in the bone defect model.
PubMed: 34840942
DOI: 10.1016/j.jobcr.2021.11.008 -
Biomolecules Nov 2023Cancer is a complex and multifaceted disease with a high global incidence and mortality rate. Although cancer therapy has evolved significantly over the years, numerous... (Review)
Review
Cancer is a complex and multifaceted disease with a high global incidence and mortality rate. Although cancer therapy has evolved significantly over the years, numerous challenges persist on the path to effectively combating this multifaceted disease. Natural compounds derived from plants, fungi, or marine organisms have garnered considerable attention as potential therapeutic agents in the field of cancer research. Ellagic acid (EA), a natural polyphenolic compound found in various fruits and nuts, has emerged as a potential cancer prevention and treatment agent. This review summarizes the experimental evidence supporting the role of EA in targeting key hallmarks of cancer, including proliferation, angiogenesis, apoptosis evasion, immune evasion, inflammation, genomic instability, and more. We discuss the molecular mechanisms by which EA modulates signaling pathways and molecular targets involved in these cancer hallmarks, based on in vitro and in vivo studies. The multifaceted actions of EA make it a promising candidate for cancer prevention and therapy. Understanding its impact on cancer biology can pave the way for developing novel strategies to combat this complex disease.
Topics: Humans; Ellagic Acid; Neoplasms; Signal Transduction; Apoptosis
PubMed: 38002335
DOI: 10.3390/biom13111653 -
Planta Medica Oct 2018Ellagic acid is a common metabolite present in many medicinal plants and vegetables. It is present either in free form or as part of more complex molecules... (Review)
Review
Ellagic acid is a common metabolite present in many medicinal plants and vegetables. It is present either in free form or as part of more complex molecules (ellagitannins), which can be metabolized to liberate ellagic acid and several of its metabolites, including urolithins. While ellagic acid's antioxidant properties are doubtless responsible for many of its pharmacological activities, other mechanisms have also been implicated in its various effects, including its ability to reduce the lipidemic profile and lipid metabolism, alter pro-inflammatory mediators (tumor necrosis factor-, interleukin-1, interleukin-6), and decrease the activity of nuclear factor-B while increasing nuclear factor erythroid 2-related factor 2 expression. These events play an important role in ellagic acid's anti-atherogenic, anti-inflammatory, and neuroprotective effects. Several of these activities, together with the effect of ellagic acid on insulin, glycogen, phosphatases, aldose reductase, sorbitol accumulation, advanced glycation end-product formation, and resistin secretion, may explain its effects on metabolic syndrome and diabetes. In addition, results from recent research have increased the interest in ellagic acid, both as a potential protective agent of the liver and skin and as a potential anticancer agent, due to the specific mechanisms affecting cell proliferation, apoptosis, DNA damage, and angiogenesis and its aforementioned anti-inflammatory properties. Taken together, these effects make ellagic acid a highly interesting compound that may contribute to different aspects of health; however, more studies are needed, especially on the compound's pharmacokinetic profile. In this review, we selected papers published from 2005 to the present.
Topics: Anti-Inflammatory Agents; Antioxidants; Apoptosis; Atherosclerosis; Cell Proliferation; Ellagic Acid; Humans; Interleukin-1beta; Interleukin-6; Metabolic Syndrome; NF-kappa B; Neuroprotection; Protective Agents; Tumor Necrosis Factor-alpha
PubMed: 29847844
DOI: 10.1055/a-0633-9492