Dietary Ellagic Acid Research Articles

Dietary ellagic acid therapy for CNS autoimmunity: Targeting on Alloprevotella rava and propionate metabolism

BackgroundMediterranean diet rich in polyphenolic compounds holds great promise to prevent and alleviate multiple sclerosis (MS), a central nervous system autoimmune disease associated with gut microbiome dysbiosis. Health-promoting effects of natural polyphenols with low bioavailability could be attributed to gut microbiota reconstruction. However, its underlying mechanism of action remains elusive, resulting in rare therapies have proposed for polyphenol-targeted modulation of gut microbiota for the treatment of MS.ResultsWe found that oral ellagic acid (EA), a natural polyphenol rich in the Mediterranean diet, effectively halted the progression of experimental autoimmune encephalomyelitis (EAE), the animal model of MS, via regulating a microbiota-metabolites-immunity axis. EA remodeled the gut microbiome composition and particularly increased the relative abundances of short-chain fatty acids -producing bacteria like Alloprevotella. Propionate (C3) was most significantly up-regulated by EA, and integrative modeling revealed a strong negative correlation between Alloprevotella or C3 and the pathological symptoms of EAE. Gut microbiota depletion negated the alleviating effects of EA on EAE, whereas oral administration of Alloprevotella rava mimicked the beneficial effects of EA on EAE. Moreover, EA directly promoted Alloprevotella rava (DSM 22548) growth and C3 production in vitro. The cell-free supernatants of Alloprevotella rava co-culture with EA suppressed Th17 differentiation by modulating acetylation in cell models. C3 can alleviate EAE development, and the mechanism may be through inhibiting HDAC activity and up-regulating acetylation thereby reducing inflammatory cytokines secreted by pathogenic Th17 cells.ConclusionsOur study identifies EA as a novel and potentially effective prebiotic for improving MS and other autoimmune diseases via the microbiota-metabolites-immunity axis.7AEBLBqRMMqqUZLLsSi8h5Video

Ellagic acid can mitigate chronic ammonia stress-induced adverse effects through the augmentation of liver autophagy in yellow catfish (Pelteobagrus fulvidraco)

The toxicity of ammonia to the majority of fish species is well-known, however, its harmful impact can be mitigated through nutritional intervention. The aim of this study was to investigate whether dietary supplementation of ellagic acid (EA) can mitigate the toxicity of chronic ammonia stress on yellow catfish. Three groups of yellow catfish were fed diets containing different concentrations of EA (0.00, 0.02, and 0.20%) for a duration of 56 days. Additionally, the fish were exposed to three different levels of ammonia (0.00, 2.50, and 25.00 mg/L total ammonia nitrogen) in order to assess any potential interactions. The results showed that ammonia toxicity could affect growth (weight gain rate and specific growth rate were decreased but feed conversion ratio declined), leads to oxidative stress (total antioxidant capacity, superoxide dismutase, and catalase decreased but H2O2 content increased), and physiological function damage (total cholesterol, total protein, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, acid phosphatase increased). Additionally, autophagy (becn1, atg3, atg4a, atg7, lc3a, and sqstm1), apoptosis (tgf-β, smad 2, caspase 3, caspase 9, and baxa), inflammation (TNF-α, IL-1β, and Myd88) related genes were up-regulated while myogenic regulatory factors (myod, myf5, myog, and igf) were down-regulated by ammonia. The inclusion of dietary EA supplementation has the potential to alleviate the detrimental impact of ammonia poisoning on fish growth, oxidative damage, physiological function impairment, and apoptotic processes by activating autophagy.

Effects of dietary addition of ellagic acid on rumen metabolism, nutrient apparent digestibility, and growth performance in Kazakh sheep.

Plant extracts have shown promise as natural feed additives to improve animal health and growth. Ellagic acid (EA), widely present in various plant tissues, offers diverse biological benefits. However, limited research has explored its effects on ruminants. This study aimed to investigate the effects of dietary addition EA on rumen metabolism, apparent digestibility of nutrients, and growth performance in Kazakh sheep. Ten 5-month-old Kazakh sheep with similar body weight (BW), fitted with rumen fistulas, were randomly assigned to two groups: the CON group (basal diet) and the EA group (basal diet + 30 mg/kg BW EA). The experiment lasted 30 days, and individual growth performance was assessed under identical feeding and management conditions. During the experimental period, rumen fluid, fecal, and blood samples were collected for analysis. The results indicated a trend toward increased average daily gain in the EA group compared to the CON group (p = 0.094). Compared with the CON group, the rumen contents of acetic acid and propionic acid were significantly increased in the EA group and reached the highest value at 2 h to 4 h after feeding (p < 0.05). Moreover, the relative abundances of specific rumen microbiota (Ruminococcaceae, uncultured_rumen_bacterium, unclassified_Prevotella, Bacteroidales, Bacteroidota, Bacteroidia, unclassified_Rikenellaceae, and Prevotella_spBP1_145) at the family and genus levels were significantly higher in the EA group (p < 0.05) compared to the CON group. The EA group exhibited significantly higher dry matter intake (p < 0.05) and increased the digestibility of neutral detergent fiber and ether extract when compared with the CON group (p < 0.05). Additionally, the plasma activities of total antioxidant capacity (T-AOC), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) were significantly higher, while malondialdehyde (MDA) concentration was significantly lower in the EA group compared to the CON group (p < 0.05). In conclusion, dietary supplementation with 30 mg/kg BW EA in 5-month-old Kazakh sheep increased the dry matter intakQ16e, apparent digestibility of neutral detergent fiber, and ether extract, as well as the contents of acetic acid and propionic acid in rumen fluid. Moreover, EA supplementation regulated the ruminal microbiota, enhanced antioxidant capacity, and improved daily weight gain.

Dietary ellagic acid blocks inflammation-associated atherosclerotic plaque formation in cholesterol-fed apoE-deficient mice.

Atherosclerosis particularly due to high circulating level of low-density lipoprotein is a major cause of cardiovascular diseases. Ellagic acid is a natural polyphenolic compound rich in pomegranates and berries. Our previous study showed that ellagic acid improved functionality of reverse cholesterol transport in murine model of atherosclerosis. The aim of this study is to investigate whether ellagic acid inhibited inflammation-associated atherosclerotic plaque formation in cholesterol-fed apolipoprotein E (apoE)-knockout (KO) mice. Wild type mice and apoE-KO mice were fed a cholesterol-rich Paigen diet for 10 weeks to induce severe atherosclerosis. Concurrently, 10 mg/kg ellagic acid was orally administered to the apoE-KO mice. Plaque lesion formation and lipid deposition were examined by staining with hematoxylin and eosin, Sudan IV and oil red O. The plasma leukocyte profile of cholesterol-fed mice was not altered by apoE deficiency. Oral administration of ellagic acid attenuated plaque lesion formation and lipid deposition in the aorta tree of apoE-KO mice. Ellagic acid substantially reduced plasma levels of soluble vascular cell adhesion molecule and interferon-γ in Paigen diet-fed apoE-KO mice. When 10 mg/kg ellagic acid was administered to cholesterol-fed apoE-KO mice, the levels of CD68 and MCP-1 were strongly reduced in aorta vessels. The protein expression level of nitric oxide synthase-2 (NOS2) in the aorta was highly enhanced by supplementation of ellagic acid to apoE-KO mice, but the expression level of heme oxygenase-1 (HO-1) in the aorta was reduced. Furthermore, ellagic acid diminished the increased aorta expression of the inflammatory adhesion molecules in cholesterol-fed apoE-KO mice. The treatment of ellagic acid inhibited the scavenger receptor-B1 expression in the aorta of apoE-KO mice, while the cholesterol efflux-related transporters were not significantly changed. These results suggest that ellagic acid may be an atheroprotective compound by attenuating apoE deficiency-induced vascular inflammation and reducing atherosclerotic plaque lesion formation.

Urolithin B: Two-way attack on IAPP proteotoxicity with implications for diabetes.

Diabetes is one of the major metabolic diseases worldwide. Despite being a complex systemic pathology, the aggregation and deposition of Islet Amyloid Polypeptide (IAPP), or amylin, is a recognized histopathological marker of the disease. Although IAPP proteotoxicity represents an important trigger of β-cell dysfunction and ultimately death, its exploitation as a therapeutic tool remains underdeveloped. The bioactivity of (poly)phenols towards inhibition of pathological protein aggregation is well known, however, most of the identified molecules have limited bioavailability. Using a strategy combining in silico, cell-free and cell studies, we scrutinized a unique in-house collection of (poly)phenol metabolites predicted to appear in the human circulation after (poly)phenols ingestion. We identified urolithin B as a potent inhibitor of IAPP aggregation and a powerful modulator of cell homeostasis pathways. Urolithin B was shown to affect IAPP aggregation pattern, delaying the formation of amyloid fibrils and altering their size and morphology. The molecular mechanisms underlying urolithin B-mediated protection include protein clearance pathways, mitochondrial function, and cell cycle ultimately rescuing IAPP-mediated cell dysfunction and death. In brief, our study uncovered urolithin B as a novel small molecule targeting IAPP pathological aggregation with potential to be exploited as a therapeutic tool for mitigating cellular dysfunction in diabetes. Resulting from the colonic metabolism of dietary ellagic acid in the human body, urolithin B bioactivity has the potential to be explored in nutritional, nutraceutical, and pharmacological perspectives.

Dietary ellagic acid supplementation attenuates intestinal damage and oxidative stress by regulating gut microbiota in weanling piglets

Intestinal oxidative stress triggers gut microbiota dysbiosis, which is involved in the etiology of post-weaning diarrhea and enteric infections. Ellagic acid (EA) can potentially serve as an antioxidant supplement to facilitate weaning transition by improving intestinal oxidative stress and gut microbiota dysbiosis. Therefore, we aimed to investigate the effects of dietary EA supplementation on the attenuation of intestinal damage, oxidative stress, and dysbiosis of gut microbiota in weanling piglets. A total of 126 piglets were randomly assigned into 3 groups and treated with a basal diet and 2mL saline orally (Ctrl group), or the basal diet supplemented with 0.1% EA and 2mL saline orally (EA group), or the basal diet and 2mL fecal microbiota suspension from the EA group orally (FEA group), respectively, for 14d. Compared with the Ctrl group, EA group improved growth performance by increasing average daily feed intake and average daily weight gain (P<0.05) and decreasing fecal scores (P<0.05). EA group also alleviated intestinal damage by increasing the tight junction protein occludin (P<0.05), villus height, and villus height-to-crypt depth ratio (P<0.05), while decreasing intestinal epithelial apoptosis (P<0.05). Additionally, EA group enhanced the jejunum antioxidant capacity by increasing the total antioxidant capacity (P<0.01), catalase (P<0.05), and glutathione/oxidized glutathione (P<0.05), but decreased the oxidative metabolite malondialdehyde (P<0.05) compared to the Ctrl group. Compared with the Ctrl group, EA and FEA groups increased alpha diversity (P<0.05), enriched beneficial bacteria (Ruminococcaceae and Clostridium ramosum), and increased metabolites short-chain fatty acids (P<0.05). Correspondingly, FEA group gained effects comparable to those of EA group on growth performance, intestinal damage, and intestinal antioxidant capacity. In addition, the relative abundance of bacteria shifted in EA and FEA groups was significantly related to the examined indices (P<0.05). Overall, dietary EA supplementation could improve growth performance and attenuate intestinal damage and oxidative stress by regulating the gut microbiota in weanling piglets.

The effects of dietary ellagic acid supplementation on growth performance, immune response, antioxidant activity, digestive enzyme activities, and intestinal functions in yellow-feathered broilers.

This study was conducted to investigate the effects of dietary supplementation with ellagic acid (EA) on the performance, immune function, antioxidant activity, digestive enzyme activities, and intestinal functions in yellow-feathered broilers. In total, 288 healthy yellow-feathered broilers with an average body weight of 39 ± 0.24 g were randomly divided into four treatment groups. Broilers were given a corn-soybean meal basal diet supplemented with 0 (control group), 100, 200, or 400 mg/kg EA. In the finisher period and the overall period, the inclusion of 100, 200, and 400 mg/kg EA increased the average daily gain (P < 0.05), and the inclusion of 200 or 400 mg/kg EA decreased the feed/gain ratio compared with the control group (P < 0.05). The best immune activity (immunoglobulin G [IgG] and immunoglobulin M [IgM] concentrations) in serum was shown in the 200 mg/kg EA group (P < 0.05). Broilers fed with 200 or 400 mg/kg EA-containing diets exhibited higher serum catalase and glutathione peroxidase activities (P < 0.05) than control broilers. The inclusion of 200 mg/kg EA in the broiler diets increased intestinal chymotrypsin, pepsin, and lipase activities (P < 0.05). Broilers fed 200 mg/kg EA-containing diets had higher villus height in the jejunum and ileum, a higher ratio between villus height and crypt depth in the jejunum, and a deeper crypt in the duodenum compared to control broilers (P < 0.05). EA reduced the diamine oxidase activity and D-lactate concentration in serum. Furthermore, in birds fed EA-containing diets, the abundance of Rikenella and norank_f_norank_o_Clostridia_UCG-014 in cecum were decreased compared with control birds (P < 0.05). Moreover, in birds fed EA-containing diets, the levels of acetate, butyrate, and total short-chain fatty acids in the cecum were higher (P < 0.05) than those in control birds. These findings indicated that dietary EA had ameliorative effects on antioxidant capability, digestive enzyme activity, immune function, and intestinal functions, which led to strengthened growth performance.

Dietary supplementation ellagic acid on the growth, intestinal immune response, microbiota, and inflammation in weaned piglets.

Piglets are susceptible to weaning stress, which weakens the barrier and immune function of the intestinal mucosa, causes inflammation, and ultimately affects animal growth and development. Ellagic acid (EA) is a natural polyphenol dilactone with various biological functions. However, The mechanisms underlying the effects of EA on animal health are still poorly known. Herein, we examined whether dietary supplementation with EA has a positive effect on growth performance, intestinal health, immune response, microbiota, or inflammation in weaned piglets. Sixty weaned piglets (age, 30 days) were randomly divided into two groups: the control group (basic diet) and the test group (basic diet + 500 g/t EA). The pigs were fed for 40 days under the same feeding and management conditions, and the growth performance of each individual was measured. At the end of the feeding period, samples were collected from the small intestinal mucosa for further analysis. Using these tissues, the transcriptome sequences and intestinal microbial diversity were analyzed in both groups. An inflammation model using small intestinal mucosal epithelial cells (IPEC-J2) was also constructed. Dietary EA supplementation significantly increased the average daily weight gain (ADG) and reduced diarrhea rate and serum diamine oxidase (DAO) levels of weaned piglets. Transcriptome sequencing results revealed 401 differentially expressed genes in the jejunum mucosal tissue of pigs in the control and test groups. Of these, 163 genes were up-regulated and 238 were down-regulated. The down-regulated genes were significantly enriched in 10 pathways (false discovery rate < 0.05), including seven pathways related to immune response. The results of bacterial 16s rDNA sequencing show that EA affects the composition of the intestinal microbiota in the cecum and rectum, and reveal significant differences in the abundances of Prevotella_9, Lactobacillus delbrueckii, and Lactobacillus reuteri between the test and control groups (P < 0.05). Experiments using the inflammation model showed that certain doses of EA promote the proliferation of IPEC-J2 cells, increase the relative mRNA expression levels of tight junction-related proteins (ZO-1 and Occludin), improve the compactness of the intestine, reduce the expression of inflammatory factors TNF-α and IL-6, and significantly reduce LPS-induced inflammation in IPEC-J2 cells. In conclusion, we found for the first time that dietary supplementation of EA affects the gut immune response and promotes the beneficial gut microbiota in weaned piglets, reduces the occurrence of inflammatory responses, and thereby promotes the growth and intestinal health of piglets.

Ellagic Acid: A Dietary-Derived Phenolic Compound for Drug Discovery in Mild Cognitive Impairment.

Ellagic acid (EA), a naturally occurring polyphenolic compound, is detected in free form or linked to polyols or sugars, constituting hydrolyzable tannins or ellagitannins in distinct fruits, nuts, and herbs. Today, a considerable number of botanicals and enriched foods containing EA are commercially available as nutraceuticals and used to prevent mild cognitive impairment (MCI) due to the excellent neuroprotective capacity of EA. Here, this study aims to provide an overview of the physicochemical properties, source, and pharmacokinetics of EA and to emphasize the importance and mechanisms of EA in the prevention and management of MCI. To date, preclinical studies of EA and its derivatives in various cell lines and animal models have advanced the idea of dietary EA as a feasible agent capable of specifically targeting and improving MCI. The molecular mechanisms of EA and its derivatives to prevent or reduce MCI are mainly through reducing neuroinflammation, oxidative stress, neuronal apoptosis, synaptic dysfunction and loss, and defective mitochondrial functions. Nevertheless, well-designed and correctly large randomized controlled trials in the human population need to be performed to reinforce the scientific facticity of the beneficial effects of EA against MCI. Synchronously, the mechanism of EA against MCI is least provided cynosure and expects more attention from the emerging research community.

Dietary Ellagic Acid Ameliorates Functionality of Reverse Cholesterol Transport in apoE-Deficient Mice

ObjectivesHigh levels of plasma LDL cholesterol are an important determinant of atherosclerotic lesion formation. The disruption of the process of cholesterol efflux or reverse cholesterol transport (RCT) of peripheral cells may promote atherogenesis. The aim of the current study was to investigate whether ellagic acid alleviated atherosclerotic development through activating RCT pathway in apoE knockout (KO) mice. MethodsWild type mice and apoE KO mice were fed high-fat high-cholesterol Paigen’s diets for 10 weeks to induce hypercholesterolemia and atherosclerosis, and concomitantly received 10 mg/kg ellagic acid via gavage. ResultsSupplying ellagic acid to apoE KO mice reduced the number of eosinophils and basophils. Ellagic acid enhanced induction of apoE and ABCG1 in oxidized LDL-exposed macrophages responsible for cholesterol efflux associated with RCT. Oral administration of ellagic acid displayed lipid-lowering effect with a reduction of atherogenic index highly elevated by Paigen’s diets in apoE KO mice. Plasma levels of cholesterol ester transport protein and phospholipid transport protein involved in RCT were elevated in mice lack of apoE gene, which was substantially reduced by supplementing ellagic acid to Paigen’s diet-fed mice. In addition, ellagic acid attenuated hepatic lipid accumulation from circulation via RCT process, evidenced by staining of H&E and Oil red O in apoE KO mice. Furthermore, the supplementation of 10 mg/kg ellagic acid favorably influenced the transcriptional levels of hepatic lipoprotein receptor of LDL receptor and scavenger receptor-B1 in Paigen’s diet-fed apoE KO mice. Finally, the signaling of PPAR-liver X receptor α appeared to be involved in the lipid-lowering ability of ellagic acid in apoE KO mice. ConclusionsEllagic acid may be an athero-protective dietary compound encumbering diet-induced atherogenesis though improving the RCT functionality. Funding SourcesThis work was supported by Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education (2021R1A6A1A03044501).

Ellagic Acid Improves Antioxidant Capacity and Intestinal Barrier Function of Heat-Stressed Broilers via Regulating Gut Microbiota.

Simple SummaryEnvironmental heat stress easily damages feed intake, intestinal health, and growth performance of broilers. Ellagic acid (EA), a natural polyphenol antioxidant in fruits or nuts, is beneficial to animal health. For the first time, we revealed that dietary EA improved antioxidant capacity and the intestinal barrier function of heat-stressed broilers probably via regulating gut microbiota. Therefore, it is proposed that EA could be exploited as a feed additive to alleviate heat stress-induced oxidative damages in broilers.Heat stress (HS) has been revealed to damage the antioxidant system and intestinal barrier function, which greatly threatens poultry production. The present study investigated the effects of dietary ellagic acid (EA) on the antioxidant system, gut barrier function, and gut microbiota of heat-stressed broilers. Arbor Acres 14-day-old broilers numbering 360 were randomly divided into six groups, including one negative control group (NC) and five experimental groups. The broilers in the NC group were supplemented with a basal diet at a normal temperature (23 ± 2 °C). The broilers in the experimental groups were supplemented with basal diets containing EA at different doses (0, 75, 150, 300, and 600 mg/kg) at HS temperature (35 ± 2 °C). The experiment lasted for 4 weeks. Results showed that dietary EA reduced the corticosterone (CORT), LPS, and diamine oxidase (DAO) levels in the serum of heat-stressed broilers. Additionally, dietary EA improved the antioxidant enzyme activity and mRNA levels of Nrf2/HO-1 in the ileum of heat-stressed broilers. The relative abundances of Streptococcus, Ruminococcus_torques, Rothia, Neisseria, Actinomyces, and Lautropia in the cecum were significantly reduced by the EA supplementation in a dose-dependent manner. Notably, the LPS, DAO, and MDA in the serum were revealed to be positively correlated with the relative abundances of Rothia, Neisseria, Actinomyces, and Lautropia, while the GSH-px, SOD, and CAT levels in the serum were negatively correlated with the relative abundances of Ruminococcus_torques, Rothia, Neisseria, Actinomyces, Streptococcus, and Lautropia. Taken together, dietary EA improved the antioxidant capacity, intestinal barrier function, and alleviated heat-stressed injuries probably via regulating gut microbiota.

Dietary ellagic acid ameliorated Clostridium perfringens-induced subclinical necrotic enteritis in broilers via regulating inflammation and cecal microbiota

BackgroundSubclinical necrotic enteritis (SNE), a common intestinal disease of broiler caused by Clostridium perfringens, could reduce production performance of broilers by chronic intestinal damage and poor absorption of nutrients. Ellagic acid (EA) has been reported to present antioxidant and anti-inflammatory properties on human and animals in many aspects. This study was conducted to evaluate the effect and mechanism of EA in relieving SNE in broilers induced by C. perfringens.ResultsC. perfringens challenge decreased body weight (BW), average daily gain (ADG), jejunal villi height/crypt depth (V/C) ratio, the activity of catalase (CAT) and the mRNA expression of zonula occludens 1 (ZO-1) in jejunal mucosa of broilers. While feed conversion ratios (FCR), jejunal crypt depth (CD), the activities of myeloperoxidase (MPO) and diamine oxidase (DAO), as well as the concentrations of interleukin 6 (IL-6), C-reactive protein (CRP) and procalcitonin (PCT) in serum, the activities of inducible nitric oxide synthase (iNOS) and lysozyme (LZM), the concentration of malondialdehyde (MDA), and the mRNA expressions of claudin-2, TNF-α, IL-1β, TLR-4, TLR-2, NF-κB, JAK3, STAT6 and iNOS in jejunal mucosa of broilers were increased by C. perfringens challenge. Dietary EA supplement relieved these adverse effects, and heightened jejunal villi height (VH), the concentration of D-xylose in plasma, activity of superoxide dismutase (SOD), and the mRNA expression of occludin in jejunal mucosa of broilers. The alpha diversity of cecal microbiota indicated that dietary EA supplement increased observed species and Shannon index. C. perfringens challenge increased the relative abundance of Firmicutes and decreased the relative abundance of Desulfobacterota in cecal microbiota. EA increased the relative abundance of Firmicutes in cecal microbiota. LEfSe analysis showed that C. perfringens challenge triggered the imbalance of cecal microbiota in broilers, dietary EA supplementation led to a small beneficial effect on microbiota, while the simultaneous effect of them seemed to stimulate the immune function of broilers by improving the microbiota balance.ConclusionsDietary EA ameliorated C. perfringens-induced SNE in broilers via regulating jejunal inflammation signaling pathways TLR/NF-κB and JAK3/STAT6, relieving jejunal oxidative stress and balancing cecal microbiota to inhibit intestinal barrier damage, prevent systemic inflammatory response and improve nutrient absorption capacity, finally protect and enhance growth performance of broilers.

Ellagic acid enhances muscle endurance by affecting the muscle fiber type, mitochondrial biogenesis and function.

Ellagic acid (EA) is a natural polyphenolic compound, which shows various effects, such as anti-inflammatory and antioxidant effects and inhibition of platelet aggregation. In this study, we investigated the effect of EA on muscle endurance and explored its possible underlying mechanism. Our data showed that EA significantly improved muscle endurance in mice. EA increased the protein level of slow myosin heavy chain (MyHC) I and decreased the protein level of fast MyHC. We also found that the AMP-activated protein kinase (AMPK) signaling pathway was activated by EA. Finally, our data indicated that EA could increase mitochondrial biogenesis and function by increasing the content of mitochondrial DNA (mtDNA), the concentration of ATP, the activities of succinodehydrogenase (SDH) and malate dehydrogenase (MDH), and the mRNA levels of ATP synthase (ATP5G), mtDNA transcription factor A (TFAM), mitochondrial transcription factor b1 (Tfb1m) and citrate synthase (Cs) in mice and C2C12 myotubes. These results proved that EA could enhance muscle endurance via transforming the muscle fiber type and improving mitochondrial biogenesis and function.

Ameliorative Effects of Dietary Ellagic Acid Against Severe Malaria Pathogenesis by Reducing Cytokine Storms and Oxidative Stress.

Ellagic acid (EA), a fruit- and vegetable-derived flavonoid, has been reported for multiple pharmacological activities, which encouraged us to examine its useful effect in severe malaria pathogenesis, especially malaria-induced cytokine storms and oxidative stress linked to damage in major organs. Malaria was induced by injecting Plasmodium berghei–infected RBCs intraperitoneally into the mice. EA was given orally (5, 10, and 20 mg/kg) following Peter’s 4-day suppression test. EA exhibited the suppression of parasitemia, production of inflammatory cytokine storms and oxidative stress marker level quantified from vital organs significantly and an increase in hemoglobin, blood glucose, and mean survival time compared to the vehicle-treated infected group. EA administration also restored the blood–brain barrier integrity evidenced through Evans blue staining. Furthermore, we demonstrated the protecting effect of EA in LPS-induced inflammatory cytokine storms and oxidative stress in glial cells. The present study conclude that ellagic acid is able to alleviate severe malaria pathogenesis by reducing cytokine storms and oxidative stress–induced by malarial parasites. It also attributed promising antimalarial activity and afforded to improve the blood glucose and hemoglobin levels in treated mice. These research findings suggested the suitability of ellagic acid as a useful bioflavonoid for further study for the management of severe malaria pathogenesis.

Ellagic acid ameliorates paraquat-induced liver injury associated with improved gut microbial profile

Paraquat, a widely used herbicide, causes environmental pollution, and liver injury in humans and animals. As a natural compound in fruits, ellagic acid (EA) shows anti-inflammatory and antioxidant effects. This study examines the beneficial effects of dietary EA against the paraquat-induced hepatic injury and further explores the underlying molecular mechanisms using a piglet model. Post-weaning piglets are fed basal diet supplemented with 50 mg/kg, 100 mg/kg, or 200 mg/kg EA for 3 weeks. At week 2, hepatic injury is induced by 4 mg/kg paraquat followed by 7 days recovery. EA supplementation significantly mitigates paraquat-induced hepatic fibrosis, steatosis, and high apoptotic rate. In agreement, EA supplementation reduces serum pro-inflammatory levels, ameliorates inflammatory cells infiltration into hepatic tissue, which are associated with suppressed NF-κB signaling during paraquat exposure. In addition, EA supplementation significantly improves activities of antioxidative enzymes which were correlated with activated Nrf2/Keap 1 signaling during paraquat exposure. Furthermore, EA supplementation restores cecal microbial community during paraquat exposure. The protective effect of EA is strongly linked with increased relative abundance of Lactobacillus reuteri and Lactobacillus amylovorus. Taken together, EA supplementation effectively reduced the occurrence of hepatic oxidative damage and inflammation induced by paraquat through modulating cecal microbial communities, which provides a novel nutritional therapeutic strategy for hepatic injury.

Pullu sazan (Cyprinus carpio Linneaus, 1758)’da ellajik asidin büyüme ve bazı antioksidan parametrelere etkisi

In the present study, it was investigated the effects of various levels of dietary ellagic acid on growth performance and antioxidant status in scaly carp (Cyprinus carpio). Fish were fed with the control diet and three different experimental diets containing three graded levels of ellagic acid (50, 100 and 200 mg kg-1 diet) for 60 days. On 30th and 60th days of experiment, the growth performance [live weight gain, relative growth and specific growth rate] and oxidant/antioxidant parameters [malondialdehyde level, catalase and glutathione-S-transferase activities and reduced glutathione level] were analysed. There was no statistically significant difference in the live weight gain, relative growth and specific growth rates of the control and ellagic acid treated groups (p &gt; 0.05). When compared to the control group, the liver and kidney malondialdehyde levels of ellagic acid treated groups were significantly decreased (p &lt; 0.05). The liver and kidney catalase and glutathione-S-transferase activities and reduced glutathione levels of ellagic acid treated groups were significantly increased when compared to the control group (p &lt; 0.05). It was concluded that ellagic acid can be used as an antioxidant in fish.

Ellagic Acid and Its Microbial Metabolite Urolithin A Alleviate Diet-Induced Insulin Resistance in Mice.

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. 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 120min 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. 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.

Gut microbial metabolites as therapeutics to treat of alcoholic liver disease

Abstract Alcoholic liver disease (ALD) is resultant of excessive consumption of alcohol. ALD is the world’s third largest risk factor for diseases and disabilities and accounting for 5.9% of all deaths worldwide. ALD patients exhibit increased gut permeability, gut microbial dysbiosis, endotoxemia and hepatic steatosis. Recent studies, unequivocally demonstrated the importance of gut microbiota and their metabolites in regulating host pathophysiology. Urolithin A (UroA) is a gut microbial metabolite derived from dietary ellagic acid and ellagitannins containing foods. Previously, we showed that UroA act as an AhR agonist and activate AhR-Nrf2 pathways to induce tight junction proteins and enhance gut barrier function. In the current study, we tested the hypothesis that correcting gut barrier dysfunction, blocking inflammation and reducing hepatic steatosis simultaneously by UroA would provide better therapeutic options to treat ALD. Our studies suggested that UroA significantly induced expression of tight junction (TJ) proteins (Occludin, Cldn4 and ZO1) in AhR-Nrf2 dependent manner and protected from alcohol-induced downregulation of TJ proteins and reduced gut barrier leakage. Further, UroA attenuated ALD pathogenesis in both acute and chronic experimental mouse models by reducing alcohol induced barrier permeability, systemic endotoxin levels and inflammatory mediators. In these models, UroA treatment also significantly reduced alcohol induced liver ALT/AST levels, inflammatory mediators (TNF-α, IL-6, IL-1β) and triglyceride levels as well as prevented liver damage. In summary, these studies highlight that the mechanisms of microbial metabolite, UroA and its multi-pronged beneficial effects in attenuating ALD.

Growth performance, haematological changes, immune response, antioxidant activity and disease resistance in rainbow trout (Oncorhynchus mykiss) fed diet supplemented with ellagic acid

The present study was performed to investigate the effects of various levels of dietary ellagic acid (EA) on growth performance, haematological values, immune response, protection against Yersinia ruckeri infection, and oxidant/antioxidant status in rainbow trout, Oncorhynchus mykiss. Fish were fed with the control diet and three different experimental diets containing three graded levels of EA (50, 100 and 200 mg kg−1 diet) for 8 weeks. At the end of the experiment, the growth performance [weight gain (WG), specific growth rate (SGR) and feed conversion ratio (FCR)], haematological values [the red blood cell (RBC) count, haemoglobin (Hb) concentration, haematocrit (Ht) level and erythrocyte indices: mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH) and mean corpuscular haemoglobin concentration (MCHC)], immune response [white blood cell (WBC) count, oxidative radical production (nitroblue tetrazolium (NBT) assay), phagocytic activity (PA) and phagocytic index (PI), total protein (TP) and immunoglobulin M (IgM) levels, serum bactericidal activity (BA), lysozyme (LYZ) and myeloperoxidase (MPO) activities] and oxidant/antioxidant status [tissue malondialdehyde (MDA) levels and superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) activities] were analysed. In addition, fish were challenged by Y. ruckeri and survival rate was recorded for 14 days. In the groups fed with EA the growth parameters such as WG, SGR, and FCR did not vary significantly. The RBC count, Hb concentration, and Ht level increased in the groups fed with EA when compared with the control group. However, there were no significant differences in the MCV, MCH and MCHC values among the groups. The results demonstrated enhancement in all the immunological parameters in the groups fed with EA compared to the control group. The results obtained from challenge with Y. ruckeri revealed reduction in the mortalities in the groups fed with EA. The dietary EA stimulated the SOD, CAT and GSH-Px activities in liver, head kidney and spleen as compared to the control group; however, a reverse trend was observed in the MDA levels of tissues. The present study suggest that EA can effectively enhance the haematological values, immune response, antioxidant capacity, and disease resistance in rainbow trout.

Effects of Black Raspberries and Their Ellagic Acid and Anthocyanin Constituents on Taxane Chemotherapy of Castration-Resistant Prostate Cancer Cells

Cancer patients often use dietary supplements while on therapy, but little is known about interactions of supplements with cancer chemotherapy. Black raspberries (BRB) have anti-cancer effects, but have not been evaluated for interference with chemotherapy for castrate-resistant prostate cancer (CRPC). Here we studied whether BRB and some of their constituents interact with docetaxel and cabazitaxel on CRPC cells in culture and implanted into nude mice. Ellagic acid increased, but BRB extract inhibited, microtubule assembly. Ellagic acid decreased tubulin polymerization by cabazitaxel and bound to tubulin. Ellagic acid, its metabolite urolithin A, BRB extract, and the anthocyanin metabolite protocatechuic acid (PCA) did not alter cytotoxicity of taxanes. Ellagic acid inhibited drug efflux in CRPC cells, but BRB extract and PCA did not. None of these compounds altered CYP3A4 activity. Although dietary ellagic acid did not alter the tumor growth inhibition by docetaxel of xenografted 22Rv1 cells, ellagic acid has the potential to interfere with taxane chemotherapy by reducing tubulin polymerization while inhibiting P-glycoprotein drug efflux. These data are cause for concern of consuming ellagic acid during treatment for CRPC and indicate need for further research, but BRB consumption appears safe.