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Besides providing nutritional value, functional foods have potential beneficial effects on health. Consumers worldwide seek food products with added value based on physical and mental well-being.This study aimed to analyze the urinary metabolome of volunteers who consumed a drink based on Costa Rican blackberries (Rubus adenotrichos) to identify the presence of urolithins and other possible bioactive compounds related to beneficial effects on health.Fifteen healthy non-smoking male volunteers aged between 19 and 43 years old who consumed 250 ml of blackberry-based drink for breakfast for eight consecutive days were selected. Urine samples were obtained before and after drink consumption, which were submitted to analysis by Ultra-Performance Liquid Chromatography coupled to a Mass Detector (UPLC/ESI-Q-TOF-MS). Subsequently, a metabolomic analysis of the results was performed to identify the presence or absence of urolithins and other bioactive metabolites related to blackberry juice consumption.It was possible to detect high intensity presence of urolithin A (n = 6) and high intensity presence of both urolithin A and B (n = 5) in urine samples in several volunteers. However, finding them was impossible in others, or they were at very low intensities (n = 4). Likewise, it was possible to identify Menth-1-en-4,8 diol glucuronide and 1-O-E-Cinnamoyl-(6-arabinosylglucose) as other compounds related to the consumption of blackberries.The consumption of Costa Rican blackberries allowed us to demonstrate the presence of three metabotypes within the study population: 40% of strong urolithin A (UAP) producers, 33.3% of both urolithin (A and B) producers (UBP), and 26.7% of weak urolithin A producers (0P). Finally, it is recommended to carry out more research in this regard, considering a greater number of volunteers and including people of both sexes. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Punica granatum L., commonly known as the pomegranate, is an abundant source of polyphenols, including hydrolyzable ellagitannins, ellagic acid, anthocyanins, and other bioactive phytochemicals shown to be effective in defending against oxidative stress, and has immunomodulatory activities. Ellagitannins, and their hydrolyzed product ellagic acid, interact with the gut microbiota to yield secondary metabolites known as urolithins that may have health benefits. The objective of this study was to determine the effects of supplementation with a standardized punicalagin-enriched pomegranate extract, Pomella® (250 mg), on the gut microbiome, circulating short-chain fatty acids, and gut microbial-derived ellagitannin metabolite urolithins. A randomized, double-blind, placebo-controlled study was conducted over 4 weeks on healthy volunteers aged 25-55 years. Subjects were randomly assigned to receive either an oral supplement containing 75 mg of punicalagin or an oral placebo. Stool sample collection and venipuncture were performed to analyze the gut microbiome, SCFAs, and urolithin. There was no significant change in the gut microbial diversity in both cohorts after 4 weeks of intervention, but there was a significantly increased relative abundance of Coprococcus eutectus, Roseburia faecis, Roseburia inullnivorans, Ruminococcus bicirculans, Ruminococcus calidus, and Faecalibacterium prausnitzii. Pomegranate extract (PE) supplementation led to the augmentation of circulating propionate levels (p = 0.02) and an increasing trend for acetate levels (p = 0.12). The pomegranate extract (PE) supplementation group had an increased level of circulating urolithins compared to the placebo group (6.6% vs. 1.1%, p = 0.13). PE supplementation correlated with shifts in the gut microbiome and with higher circulating levels of propionate and acetate. Further studies should explore the implications in larger cohorts and over a longer duration.

In the present review, we discuss the occurrence of ellagitannins (ETs) and ellagic acid (EA) and methods for their isolation from plant materials. We summarize analytical methods, including high-performance liquid chromatography–ultraviolet (HPLC–UV) and liquid chromatography–mass spectrometry (LC–MS), for the determination of ETs, EA and their bioactive metabolites urolithins (Uros) in samples of plant and food origin, as well as in biological samples, such as plasma, urine and feces. In addition, the current interest in the bioactivities of Uros is discussed in brief. [ABSTRACT FROM AUTHOR]

Obesity is in epidemic proportions in many parts of the world, contributing to increasing rates of non-alcoholic fatty liver disease (NAFLD). NAFLD represents a range of conditions from the initial stage of fatty liver to non-alcoholic steatohepatitis (NASH), which can progress to severe fibrosis, through to hepatocellular carcinoma. There currently exists no treatment for the long-term management of NAFLD/NASH, however, dietary interventions have been investigated for the treatment of NASH, including several polyphenolic compounds. Ellagic acid is one such polyphenolic compound. Nutraceutical food abundant in ellagic acid undergoes initial hydrolysis to free ellagic acid within the stomach and small intestine. The proposed mechanism of action of ellagic acid extends beyond its initial therapeutic potential, as it is further broken down by the gut microbiome into urolithin. Both ellagic acid and urolithin have been found to alleviate oxidative stress, inflammation, and fibrosis, which are associated with NAFLD/NASH. While progress has been made in understanding the pharmacological and biological activity of ellagic acid and its involvement in NAFLD/NASH, it has yet to be fully elucidated. Thus, the aim of this review is to summarise the currently available literature elucidating the therapeutic potential of ellagic acid and its microbial-derived metabolite urolithin in NAFLD/NASH. [ABSTRACT FROM AUTHOR]

Inflammation and oxidative stress (OS) are crucial processes essential in various physiological and pathological states. The imbalance in reactive oxygen species (ROS) interrupts the body’s natural defense system, making fatal disorders more likely to develop. Walnut, also known as Juglans Regia L. is a valuable nut that can significantly reduce OS and inflammation. Walnut contains a considerable amount of polyunsaturated fatty acids (PUFA), flavonoids and phenolic compounds, specifically ellagitannins, that have emerged as major anti-oxidative and anti-inflammatory contributors by activating the Nrf2 signaling pathway. Moreover, quercetin, gallic acid, epigallocatechin-3-gallate and chlorogenic acid scavenge free radicals, modulate pro-inflammatory pathways and suppress the production of inflammatory cytokines. Currently, there is a limited compilation of previous research studies on walnut’s anti-oxidative and anti-inflammatory potential, along with their curative insights against other physiological conditions. This review presents an overview of the latest research studies of walnuts in different forms, as a whole, its extract, oil, protein hydrolysate, peptides, etc., supporting its antioxidant and anti-inflammatory potential in tabular form, along with the figures to demonstrate the underlying mechanisms of its active components through animal and clinical trials. The regulatory effects of the bioactive substances against hyperlipidemia, diabetes, arthritis, Alzheimer’s, seizures, hypertension, ischemic stroke, and cancer have also been elaborated. The findings of the present compilation of research studies suggest that walnuts have a remarkable potential to alleviate oxidative stress and inflammation due to its high concentration of bioactive compounds, by activating the Nrf2 signaling pathway, scavenging free radicals, and modify pro-inflammatory pathways. The incorporation of walnuts in daily diet is an effective therapeutic approach to support overall health and wellness.

Abstract Background Despite rising public awareness and improvements in diagnostic and treatment methods, there are adverse effects brought on by drug resistance, an increase in overall treatment costs, and unanticipated side effects from pharmaceuticals. Main body Therefore, efforts for development strategy that is more efficient, more affordable, and more secure are underway. Such a strategy involves employing naturally occurring phytochemicals to delay the beginning, prevent it from happening, or treat it, and it sparks an increase in interest in studies looking for an effective agent in herbs and other plant materials used in traditional medicines. Urolithins are polyphenol chemicals generated by the gut microbiota studied for potential health benefits and have a high bioavailability. After being ingested, urolithins can move throughout the body and mediate in different locations. Urolithins are studied for over 40 years, but their mechanistic role has been explored recently in understanding their potential health benefits. Short conclusion This review gives an overview of the current Urolithin A research on human health. The findings highlight the importance of exploring the potential of urolithins as a natural compound for therapeutic applications. Elucidating the mechanisms behind the disease process and pinpointing candidate molecules and pathways to target preventive and therapeutic intervention are the need of the hour.

Background: Despite rising public awareness and improvements in diagnostic and treatment methods, there are adverse effects brought on by drug resistance, an increase in overall treatment costs, and unanticipated side effects from pharmaceuticals. Main body: Therefore, efforts for development strategy that is more efficient, more affordable, and more secure are underway. Such a strategy involves employing naturally occurring phytochemicals to delay the beginning, prevent it from happening, or treat it, and it sparks an increase in interest in studies looking for an effective agent in herbs and other plant materials used in traditional medicines. Urolithins are polyphenol chemicals generated by the gut microbiota studied for potential health benefits and have a high bioavailability. After being ingested, urolithins can move throughout the body and mediate in different locations. Urolithins are studied for over 40 years, but their mechanistic role has been explored recently in understanding their potential health benefits. Short conclusion: This review gives an overview of the current Urolithin A research on human health. The findings highlight the importance of exploring the potential of urolithins as a natural compound for therapeutic applications. Elucidating the mechanisms behind the disease process and pinpointing candidate molecules and pathways to target preventive and therapeutic intervention are the need of the hour. [ABSTRACT FROM AUTHOR]

Ellagitannins are vital bioactive polyphenols that are widely distributed in a variety of plant-based foods. The main metabolites of ellagitannins are urolithins, and current research suggests that urolithins provide a variety of health benefits. This review focused on the role of the gut bacteria in the conversion of ellagitannins to urolithins. Based on the results of in vitro and in vivo studies, the health benefits of urolithins, including antioxidant, anti-inflammatory, anti-cancer, anti-obesity, anti-diabetic, anti-aging, cardiovascular protective, neuroprotective, kidney protective, and muscle mass protective effects, were thoroughly outlined, with a focus on their associated molecular mechanisms. Finally, we briefly commented on urolithins' safety. Overall, urolithins' diverse health benefits indicate the potential utilization of ellagitannins and urolithins in the creation of functional foods and nutraceuticals to treat and prevent some chronic diseases. [ABSTRACT FROM AUTHOR]

Punica granatum L., commonly known as the pomegranate, is an abundant source of polyphenols, including hydrolyzable ellagitannins, ellagic acid, anthocyanins, and other bioactive phytochemicals shown to be effective in defending against oxidative stress, and has immunomodulatory activities. Ellagitannins, and their hydrolyzed product ellagic acid, interact with the gut microbiota to yield secondary metabolites known as urolithins that may have health benefits. The objective of this study was to determine the effects of supplementation with a standardized punicalagin-enriched pomegranate extract, Pomella® (250 mg), on the gut microbiome, circulating short-chain fatty acids, and gut microbial-derived ellagitannin metabolite urolithins. A randomized, double-blind, placebo-controlled study was conducted over 4 weeks on healthy volunteers aged 25–55 years. Subjects were randomly assigned to receive either an oral supplement containing 75 mg of punicalagin or an oral placebo. Stool sample collection and venipuncture were performed to analyze the gut microbiome, SCFAs, and urolithin. There was no significant change in the gut microbial diversity in both cohorts after 4 weeks of intervention, but there was a significantly increased relative abundance of Coprococcus eutectus, Roseburia faecis, Roseburia inullnivorans, Ruminococcus bicirculans, Ruminococcus calidus, and Faecalibacterium prausnitzii. Pomegranate extract (PE) supplementation led to the augmentation of circulating propionate levels (p = 0.02) and an increasing trend for acetate levels (p = 0.12). The pomegranate extract (PE) supplementation group had an increased level of circulating urolithins compared to the placebo group (6.6% vs. 1.1%, p = 0.13). PE supplementation correlated with shifts in the gut microbiome and with higher circulating levels of propionate and acetate. Further studies should explore the implications in larger cohorts and over a longer duration. [ABSTRACT FROM AUTHOR]

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.

Non-structural protein 5 (Nsp5) is a cysteine protease that plays a key role in SARS-CoV-2 replication, suppressing host protein synthesis and promoting immune evasion. The investigation of natural products as a potential strategy for Nsp5 inhibition is gaining attention as a means of developing antiviral agents. In this work, we have investigated the physicochemical properties and structure-activity relationships of ellagic acid and its gut metabolites, urolithins A–D, as ligands of Nsp5. Results allow us to identify urolithin D as promising ligand of Nsp5, with a dissociation constant in the nanomolar range of potency. Although urolithin D is able to bind to the catalytic cleft of Nsp5, the appraisal of its viral replication inhibition against SARS-CoV-2 in Vero E6 assay highlights a lack of activity. While these results are discussed in the framework of the available literature reporting conflicting data on polyphenol antiviral activity, they provide new clues for natural products as potential viral protease inhibitors. [ABSTRACT FROM AUTHOR]

We previously reported that proinflammatory cytokines, particularly tumor necrosis factor (TNF)-α, promoted tumor migration, invasion, and proliferation, thus worsening the prognosis of glioblastoma (GBM). Urolithins, the potent metabolites produced by the gut from pomegranate polyphenols, have anticancer properties. To develop an effective therapy for GBM, this study aimed to study the effects of urolithins against GBM. Urolithin A and B significantly reduced GBM migration, reduced epithelial–mesenchymal transition, and inhibited tumor growth. Moreover, urolithin A and B inhibited TNF-α-induced vascular cell adhesion molecule (VCAM)-1 and programmed death ligand 1 (PD-L1) expression, thereby reducing human monocyte (HM) binding to GBM cells. Aryl hydrocarbon receptor (AhR) level had higher expression in patients with glioma than in healthy individuals. Urolithins are considered pharmacological antagonists of AhR. We demonstrated that the inhibition of AhR reduced TNF-α-stimulated VCAM-1 and PD-L1 expression. Furthermore, human macrophage condition medium enhanced expression of PD-L1 in human GBM cells. Administration of the AhR antagonist attenuated the enhancement of PD-L1, indicating the AhR modulation in GBM progression. The modulatory effects of urolithins in GBM involve inhibiting the Akt and epidermal growth factor receptor pathways. The present study suggests that urolithins can inhibit GBM progression and provide valuable information for anti-GBM strategy. [ABSTRACT FROM AUTHOR]

Abstract Background Epigenetic age is an estimator of biological age based on DNA methylation; its discrepancy from chronologic age warrants further investigation. We recently reported that greater polyphenol intake benefitted ectopic fats, brain function, and gut microbiota profile, corresponding with elevated urine polyphenols. The effect of polyphenol-rich dietary interventions on biological aging is yet to be determined. Methods We calculated different biological aging epigenetic clocks of different generations (Horvath2013, Hannum2013, Li2018, Horvath skin and blood2018, PhenoAge2018, PCGrimAge2022), their corresponding age and intrinsic age accelerations, and DunedinPACE, all based on DNA methylation (Illumina EPIC array; pre-specified secondary outcome) for 256 participants with abdominal obesity or dyslipidemia, before and after the 18-month DIRECT PLUS randomized controlled trial. Three interventions were assigned: healthy dietary guidelines, a Mediterranean (MED) diet, and a polyphenol-rich, low-red/processed meat Green-MED diet. Both MED groups consumed 28 g walnuts/day (+ 440 mg/day polyphenols). The Green-MED group consumed green tea (3–4 cups/day) and Mankai (Wolffia globosa strain) 500-ml green shake (+ 800 mg/day polyphenols). Adherence to the Green-MED diet was assessed by questionnaire and urine polyphenols metabolomics (high-performance liquid chromatography quadrupole time of flight). Results Baseline chronological age (51.3 ± 10.6 years) was significantly correlated with all methylation age (mAge) clocks with correlations ranging from 0.83 to 0.95; p

In the present review, we discuss the occurrence of ellagitannins (ETs) and ellagic acid (EA) and methods for their isolation from plant materials. We summarize analytical methods, including high-performance liquid chromatography–ultraviolet (HPLC–UV) and liquid chromatography–mass spectrometry (LC–MS), for the determination of ETs, EA and their bioactive metabolites urolithins (Uros) in samples of plant and food origin, as well as in biological samples, such as plasma, urine and feces. In addition, the current interest in the bioactivities of Uros is discussed in brief.

Obesity is in epidemic proportions in many parts of the world, contributing to increasing rates of non-alcoholic fatty liver disease (NAFLD). NAFLD represents a range of conditions from the initial stage of fatty liver to non-alcoholic steatohepatitis (NASH), which can progress to severe fibrosis, through to hepatocellular carcinoma. There currently exists no treatment for the long-term management of NAFLD/NASH, however, dietary interventions have been investigated for the treatment of NASH, including several polyphenolic compounds. Ellagic acid is one such polyphenolic compound. Nutraceutical food abundant in ellagic acid undergoes initial hydrolysis to free ellagic acid within the stomach and small intestine. The proposed mechanism of action of ellagic acid extends beyond its initial therapeutic potential, as it is further broken down by the gut microbiome into urolithin. Both ellagic acid and urolithin have been found to alleviate oxidative stress, inflammation, and fibrosis, which are associated with NAFLD/NASH. While progress has been made in understanding the pharmacological and biological activity of ellagic acid and its involvement in NAFLD/NASH, it has yet to be fully elucidated. Thus, the aim of this review is to summarise the currently available literature elucidating the therapeutic potential of ellagic acid and its microbial-derived metabolite urolithin in NAFLD/NASH.

Non-structural protein 5 (Nsp5) is a cysteine protease that plays a key role in SARS-CoV-2 replication, suppressing host protein synthesis and promoting immune evasion. The investigation of natural products as a potential strategy for Nsp5 inhibition is gaining attention as a means of developing antiviral agents. In this work, we have investigated the physicochemical properties and structure-activity relationships of ellagic acid and its gut metabolites, urolithins A–D, as ligands of Nsp5. Results allow us to identify urolithin D as promising ligand of Nsp5, with a dissociation constant in the nanomolar range of potency. Although urolithin D is able to bind to the catalytic cleft of Nsp5, the appraisal of its viral replication inhibition against SARS-CoV-2 in Vero E6 assay highlights a lack of activity. While these results are discussed in the framework of the available literature reporting conflicting data on polyphenol antiviral activity, they provide new clues for natural products as potential viral protease inhibitors.

Background: Epigenetic age is an estimator of biological age based on DNA methylation; its discrepancy from chronologic age warrants further investigation. We recently reported that greater polyphenol intake benefitted ectopic fats, brain function, and gut microbiota profile, corresponding with elevated urine polyphenols. The effect of polyphenol-rich dietary interventions on biological aging is yet to be determined. Methods: We calculated different biological aging epigenetic clocks of different generations (Horvath2013, Hannum2013, Li2018, Horvath skin and blood2018, PhenoAge2018, PCGrimAge2022), their corresponding age and intrinsic age accelerations, and DunedinPACE, all based on DNA methylation (Illumina EPIC array; pre-specified secondary outcome) for 256 participants with abdominal obesity or dyslipidemia, before and after the 18-month DIRECT PLUS randomized controlled trial. Three interventions were assigned: healthy dietary guidelines, a Mediterranean (MED) diet, and a polyphenol-rich, low-red/processed meat Green-MED diet. Both MED groups consumed 28 g walnuts/day (+ 440 mg/day polyphenols). The Green-MED group consumed green tea (3–4 cups/day) and Mankai (Wolffia globosa strain) 500-ml green shake (+ 800 mg/day polyphenols). Adherence to the Green-MED diet was assessed by questionnaire and urine polyphenols metabolomics (high-performance liquid chromatography quadrupole time of flight). Results: Baseline chronological age (51.3 ± 10.6 years) was significantly correlated with all methylation age (mAge) clocks with correlations ranging from 0.83 to 0.95; p < 2.2e − 16 for all. While all interventions did not differ in terms of changes between mAge clocks, greater Green-Med diet adherence was associated with a lower 18-month relative change (i.e., greater mAge attenuation) in Li and Hannum mAge (beta = − 0.41, p = 0.004 and beta = − 0.38, p = 0.03, respectively; multivariate models). Greater Li mAge attenuation (multivariate models adjusted for age, sex, baseline mAge, and weight loss) was mostly affected by higher intake of Mankai (beta = − 1.8; p = 0.061) and green tea (beta = − 1.57; p = 0.0016) and corresponded with elevated urine polyphenols: hydroxytyrosol, tyrosol, and urolithin C (p < 0.05 for all) and urolithin A (p = 0.08), highly common in green plants. Overall, participants undergoing either MED-style diet had ~ 8.9 months favorable difference between the observed and expected Li mAge at the end of the intervention (p = 0.02). Conclusions: This study showed that MED and green-MED diets with increased polyphenols intake, such as green tea and Mankai, are inversely associated with biological aging. To the best of our knowledge, this is the first clinical trial to indicate a potential link between polyphenol intake, urine polyphenols, and biological aging. Trial registration: ClinicalTrials.gov, NCT03020186. [ABSTRACT FROM AUTHOR]

Pomegranate fruit (PF) is a fruit rich in nutraceuticals. Nonedible parts of the fruit, especially peels, contain high amounts of bioactive components that have been largely used in traditional medicine, such as the Chinese, Unani, and Ayurvedic ones, for treating several diseases. Polyphenols such as anthocyanins, tannins, flavonoids, phenolic acids, and lignans are the major bioactive molecules present in PF. Therefore, PF is considered a source of natural multifunctional agents that exert simultaneously antioxidant, anti-inflammatory, antitumor, antidiabetic, cardiovascular, and neuroprotective activities. Recently, several studies have reported that the nutraceuticals contained in PF (seed, peel, and juice) have a potential beneficial role in Alzheimer's disease (AD). Research suggests that the neuroprotective effect of PF is mostly due to its potent antioxidant and anti-inflammatory activities which contribute to attenuate the neuroinflammation associated with AD. Despite the numerous works conducted on PF, to date the mechanism by which PF acts in combatting AD is not completely known. Here, we summarize all the recent findings (in vitro and in vivo studies) related to the positive effects that PF and its bioactive components can have in the neurodegeneration processes occurring during AD. Moreover, considering the high biotransformation characteristics of the nutraceuticals present in PF, we propose to consider the chemical structure of its active metabolites as a source of inspiration to design new molecules with the same beneficial effects but less prone to be affected by the metabolic degradation process. [ABSTRACT FROM AUTHOR]

Atherosclerotic cardiovascular disease (ACVD) is the leading cause of death worldwide. Although current therapies, such as statins, have led to a marked reduction in morbidity and mortality from ACVD, they are associated with considerable residual risk for the disease together with various adverse side effects. Natural compounds are generally well-tolerated; a major recent goal has been to harness their full potential in the prevention and treatment of ACVD, either alone or together with existing pharmacotherapies. Punicalagin (PC) is the main polyphenol present in pomegranates and pomegranate juice and demonstrates many beneficial actions, including anti-inflammatory, antioxidant, and anti-atherogenic properties. The objective of this review is to inform on our current understanding of the pathogenesis of ACVD and the potential mechanisms underlying the beneficial actions of PC and its metabolites in the disease, including the attenuation of dyslipidemia, oxidative stress, endothelial cell dysfunction, foam cell formation, and inflammation mediated by cytokines and immune cells together with the regulation of proliferation and migration of vascular smooth muscle cells. Some of the anti-inflammatory and antioxidant properties of PC and its metabolites are due to their strong radical-scavenging activities. PC and its metabolites also inhibit the risk factors of atherosclerosis, including hyperlipidemia, diabetes mellitus, inflammation, hypertension, obesity, and non-alcoholic fatty liver disease. Despite the promising findings that have emerged from numerous in vitro, in vivo, and clinical studies, deeper mechanistic insights and large clinical trials are required to harness the full potential of PC and its metabolites in the prevention and treatment of ACVD. [ABSTRACT FROM AUTHOR]

In this work, quantum chemical calculations based on density functional theory (DFT) were performed to predict the antioxidant potential of four bioactive gut microbiota metabolites of the natural polyphenols ellagitannins (ETs) and ellagic acid (EA), also known as urolithins (UROs). In order to evaluate their ability to counter the effect of oxidative stress caused by reactive oxygen species (ROS), such as the hydroperoxyl radical (•OOH), different reaction mechanisms were investigated, considering water and lipid-like environments. Through our in silico results, it emerged that at physiological pH, the scavenging activity of all urolithins, except urolithin B, are higher than that of trolox and other potent antioxidants existing in nature, such as EA, α-mangostin, allicin, caffeine and melatonin. These findings were confirmed by experimental assays. [ABSTRACT FROM AUTHOR]

Flavonoids are a biodiverse family of dietary compounds that have antioxidant, anti-inflammatory, antiviral, and antibacterial cell protective profiles. They have received considerable attention as potential therapeutic agents in biomedicine and have been widely used in traditional complimentary medicine for generations. Such complimentary medical herbal formulations are extremely complex mixtures of many pharmacologically active compounds that provide a therapeutic outcome through a network pharmacological effects of considerable complexity. Methods are emerging to determine the active components used in complimentary medicine and their therapeutic targets and to decipher the complexities of how network pharmacology provides such therapeutic effects. The gut microbiome has important roles to play in the generation of bioactive flavonoid metabolites retaining or exceeding the antioxidative and anti-inflammatory properties of the intact flavonoid and, in some cases, new antitumor and antineurodegenerative bioactivities. Certain food items have been identified with high prebiotic profiles suggesting that neutraceutical supplementation may be beneficially employed to preserve a healthy population of bacterial symbiont species and minimize the establishment of harmful pathogenic organisms. Gut health is an important consideration effecting the overall health and wellbeing of linked organ systems. Bioconversion of dietary flavonoid components in the gut generates therapeutic metabolites that can also be transported by the vagus nerve and systemic circulation to brain cell populations to exert a beneficial effect. This is particularly important in a number of neurological disorders (autism, bipolar disorder, AD, PD) characterized by effects on moods, resulting in depression and anxiety, impaired motor function, and long-term cognitive decline. Native flavonoids have many beneficial properties in the alleviation of inflammation in tissues, however, concerns have been raised that therapeutic levels of flavonoids may not be achieved, thus allowing them to display optimal therapeutic effects. Dietary manipulation and vagal stimulation have both yielded beneficial responses in the treatment of autism spectrum disorders, depression, and anxiety, establishing the vagal nerve as a route of communication in the gut-brain axis with established roles in disease intervention. While a number of native flavonoids are beneficial in the treatment of neurological disorders and are known to penetrate the blood–brain barrier, microbiome-generated flavonoid metabolites (e.g., protocatechuic acid, urolithins, γ-valerolactones), which retain the antioxidant and anti-inflammatory potency of the native flavonoid in addition to bioactive properties that promote mitochondrial health and cerebrovascular microcapillary function, should also be considered as potential biotherapeutic agents. Studies are warranted to experimentally examine the efficacy of flavonoid metabolites directly, as they emerge as novel therapeutic options. [ABSTRACT FROM AUTHOR]

Liver pyruvate kinase (PKL) has recently emerged as a new target for non-alcoholic fatty liver disease (NAFLD), and inhibitors of this enzyme could represent a new therapeutic option. However, this breakthrough is complicated by selectivity issues since pyruvate kinase exists in four different isoforms. In this work, we report that ellagic acid (EA) and its derivatives, present in numerous fruits and vegetables, can inhibit PKL potently and selectively. Several polyphenolic analogues of EA were synthesized and tested to identify the chemical features responsible for the desired activity. Molecular modelling studies suggested that this inhibition is related to the stabilization of the PKL inactive state. This unique inhibition mechanism could potentially herald the development of new therapeutics for NAFLD. [ABSTRACT FROM AUTHOR]

Ellagitannins (ETs) are a large group of bioactive compounds found in plant-source foods, such as pomegranates, berries, and nuts. The consumption of ETs has often been associated with positive effects on many pathologies, including cardiovascular diseases, neurodegenerative syndromes, and cancer. Although multiple biological activities (antioxidant, anti-inflammatory, chemopreventive) have been discussed for ETs, their limited bioavailability prevents reaching significant concentrations in systemic circulation. Instead, urolithins, ET gut microbiota-derived metabolites, are better absorbed and could be the bioactive molecules responsible for the antioxidant and anti-inflammatory activities or anti-tumor cell progression. In this review, we examined the dietary sources, metabolism, and bioavailability of ETs, and analyzed the last recent findings on ETs, ellagic acid, and urolithins, their intestinal and brain activities, the potential mechanisms of action, and the connection between the ET microbiota metabolism and the consequences detected on the gut–brain axis. The current in vitro, in vivo, and clinical studies indicate that ET-rich foods, individual gut microbiomes, or urolithin types could modulate signaling pathways and promote beneficial health effects. A better understanding of the role of these metabolites in disease pathogenesis may assist in the prevention or treatment of pathologies targeting the gut–brain axis. [ABSTRACT FROM AUTHOR]

Urolithins are the gut microbiota metabolites of ellagitannins which are found in natural plants such as pomegranate, strawberry, and raspberry, and in nuts. Recently, several reports have clarified the underlying mechanism of urolithins in central nervous system inflammation. Therefore, urolithins have become potential therapeutic drug candidate molecules for central nervous system diseases. Derivatives 1–1d, 1–1f, 3–2a, and 3–2b of urolithin A, urolithin B, and methoxyurolithin A were found to have had significant inhibitory activity against phosphodiesterase II with IC50 values of 35.42, 39.96, 25.58, and 13.84 μM, respectively. Herein, we report the design and synthesis of urolithin derivatives along with a biological evaluation of their activity against phosphodiesterase II. [ABSTRACT FROM AUTHOR]

We previously reported that proinflammatory cytokines, particularly tumor necrosis factor (TNF)-α, promoted tumor migration, invasion, and proliferation, thus worsening the prognosis of glioblastoma (GBM). Urolithins, the potent metabolites produced by the gut from pomegranate polyphenols, have anticancer properties. To develop an effective therapy for GBM, this study aimed to study the effects of urolithins against GBM. Urolithin A and B significantly reduced GBM migration, reduced epithelial–mesenchymal transition, and inhibited tumor growth. Moreover, urolithin A and B inhibited TNF-α-induced vascular cell adhesion molecule (VCAM)-1 and programmed death ligand 1 (PD-L1) expression, thereby reducing human monocyte (HM) binding to GBM cells. Aryl hydrocarbon receptor (AhR) level had higher expression in patients with glioma than in healthy individuals. Urolithins are considered pharmacological antagonists of AhR. We demonstrated that the inhibition of AhR reduced TNF-α-stimulated VCAM-1 and PD-L1 expression. Furthermore, human macrophage condition medium enhanced expression of PD-L1 in human GBM cells. Administration of the AhR antagonist attenuated the enhancement of PD-L1, indicating the AhR modulation in GBM progression. The modulatory effects of urolithins in GBM involve inhibiting the Akt and epidermal growth factor receptor pathways. The present study suggests that urolithins can inhibit GBM progression and provide valuable information for anti-GBM strategy.

Urolithins, including urolithin A (Uro-A), are metabolites of ellagitannins (ETs) and ellagic acid (EA) produced by gut bacterial metabolism and exhibit multifarious health-promoting bioactivities. As the capacity to produce urolithins varies widely among individuals, identifying urolithin-producing bacteria and elucidating the metabolic pathways from EA to Uro-A have garnered intense research attention worldwide. This review discusses the latest advancements in the identification of bacterial strains capable of converting EA into Uro-A, and the development of functional foods enriched in Uro-A. Topics covered include the approaches for screening of urolithin-producing bacteria, optimization of fermentation processes, analysis of metabolic pathways, and the employment of gene editing and synthetic biology techniques. Moreover, the development and industrialization of Uro-A-enriched functional foods, and the discovery of next-generation probiotics are also explored. Bacteria capable of producing Uro-A can be employed for producing fermented functional foods. As the novel multi-subunit molybdoenzyme is only present in specific gut bacteria, for example Lachnospiraceae spp., for converting Uro-C to Uro-A, gene editing and synthetic biology techniques can be applied to substantially enhance the efficiency of Uro-A production. On top of this, this review also sheds light on a few future research directions, including strategies to improve the yield and consistency of Uro-A production, and expansion of its applications in health-related industries. • Bacteria involved in EA metabolism to urolithins are overviewed. • Uro-A showed many biological activities. • The pathways associated with transformation of EA to urolithins are highlighted. • The possible applications of bacteria transforming EA to Uro-A are discussed. [ABSTRACT FROM AUTHOR]

[Display omitted] • Antiradical activity of urolithins (UroA, UroB, UroC and UroD) explored in the non-polar medium. • The reactivity of urolithins towards radicals decreases in the following order UroD > UroC > UroA > UroB. • Urolithins regenerate glutathione by donating hydrogen atoms to glutathione radicals. • Urolithine radicals exhibit reduced reactivity towards fatty acid models compared to reactive oxygen radical species. • Urolithins show similar inhibitory activity as conventional inhibitors on the Xanthine Dehydrogenase (XDH) enzyme. This work aimed to explore the antiradical activity of various ellagitannin metabolites, including Urolithin A (UroA), Urolithin B (UroB), Urolithin C (UroC), and Urolithin D (UroD), in a non-polar (benzene) and polar (water) medium. The antiradical effect of the investigated compounds against reactive oxygen species HO• was evaluated in water (physiological conditions) and benzene, while against CH 3 OO• and CCl 3 OO• it was assessed solely in benzene, using the Quantum Mechanics-based Test for Overall Free-radical Scavenging Activity (QM-ORSA) methodology. In non-polar media, compounds UroA , UroC , and UroD exhibit antiradical capabilities against the HO• through Proton-coupled electron transfer (PCET) and Radical Adduct Formation (RAF) processes. Conversely, UroB predominantly exhibits inhibitory activity on HO• through the RAF pathway. On the other hand, the reaction with CH 3 OO• and CCl 3 OO• only occurs through the Hydrogen Atom Transfer (HAT). Under physiological conditions, all investigated compounds show antiradical capacity against the HO•, primarily via the SPLET and RCF mechanisms. The reactivity of radical species in both solvents decreases in the following order: HO• > CCl 3 OO• > CH 3 OO•. The thermodynamic and kinetic parameters in both solvents indicate that the investigated compounds' reactivity follows a decreasing order of UroD > UroA > UroC > UroB. Furthermore, newly formed radical species of urolithin exhibit lower reactivity towards the fatty acid model in comparison to investigated reactive radical species, potentially preventing lipid peroxidation initiation. The investigated compounds can regenerate glutathione (GSH) by providing a hydrogen atom to the glutathione radical (GS•), which forms during interaction with highly reactive radical species. In water, tested compounds also regenerate GSH by donating H atoms to GS•, as well as by transferring electrons from dominant acid-base species to GS•, followed by protonation of the resulting GS¯. Urolithins showed similar inhibitory effects as the conventional inhibitors Y-700, FYX-051, and Febuxostat on Xanthine Dehydrogenase (XDH). Reactivity towards XDH enzyme decreases in the following order UroC > UroB > UroD > UroA. [ABSTRACT FROM AUTHOR]

[Display omitted] • Walnuts contain polyunsaturated fatty acids and polyphenols, abundantly ellagitannin. • Ellagitannin exhibits antioxidant and anti-inflammatory properties. • Reduces oxidative stress by activating the Nrf2 signalling pathway. • A balanced diet containing walnuts improves general well-being. Inflammation and oxidative stress (OS) are crucial processes essential in various physiological and pathological states. The imbalance in reactive oxygen species (ROS) interrupts the body's natural defense system, making fatal disorders more likely to develop. Walnut, also known as Juglans Regia L. is a valuable nut that can significantly reduce OS and inflammation. Walnut contains a considerable amount of polyunsaturated fatty acids (PUFA), flavonoids and phenolic compounds, specifically ellagitannins, that have emerged as major anti-oxidative and anti-inflammatory contributors by activating the Nrf2 signaling pathway. Moreover, quercetin, gallic acid, epigallocatechin-3-gallate and chlorogenic acid scavenge free radicals, modulate pro-inflammatory pathways and suppress the production of inflammatory cytokines. Currently, there is a limited compilation of previous research studies on walnut's anti-oxidative and anti-inflammatory potential, along with their curative insights against other physiological conditions. This review presents an overview of the latest research studies of walnuts in different forms, as a whole, its extract, oil, protein hydrolysate, peptides, etc., supporting its antioxidant and anti-inflammatory potential in tabular form, along with the figures to demonstrate the underlying mechanisms of its active components through animal and clinical trials. The regulatory effects of the bioactive substances against hyperlipidemia, diabetes, arthritis, Alzheimer's, seizures, hypertension, ischemic stroke, and cancer have also been elaborated. The findings of the present compilation of research studies suggest that walnuts have a remarkable potential to alleviate oxidative stress and inflammation due to its high concentration of bioactive compounds, by activating the Nrf2 signaling pathway, scavenging free radicals, and modify pro-inflammatory pathways. The incorporation of walnuts in daily diet is an effective therapeutic approach to support overall health and wellness. [ABSTRACT FROM AUTHOR]

Urolithins are bioactive compounds generated in human and animal intestines because of the bacterial metabolism of dietary ellagitannins (and their constituent, ellagic acid). Due to their multidirectional effects, including anti-inflammatory, antioxidant, anti-cancer, neuroprotective, and antiglycative properties, urolithins are potential novel therapeutic agents. In this study, while considering the future possibility of using urolithins to improve podocyte function in diabetes, we assessed the results of exposing mouse podocytes cultured in normal (NG, 5.5 mM) and high (HG, 25 mM) glucose concentrations to urolithin A (UA) and urolithin B (UB). Podocytes metabolized UA to form glucuronides in a time-dependent manner; however, in HG conditions, the metabolism was lower than in NG conditions. In HG milieu, UA improved podocyte viability more efficiently than UB and reduced the reactive oxygen species level. Both types of urolithins showed cytotoxic activity at high (100 µM) concentration. The UA upregulated total and surface nephrin expression, which was paralleled by enhanced nephrin internalization. Regulation of nephrin turnover was independent of ambient glucose concentration. We conclude that UA affects podocytes in different metabolic and functional aspects. With respect to its pro-survival effects in HG-induced toxicity, UA could be considered as a potent therapeutic candidate against diabetic podocytopathy. [ABSTRACT FROM AUTHOR]

Background: An incorrect lifestyle, including diet, is responsible for the worldwide dramatic increase in obesity and type 2 diabetes. Increasing dietary fiber consumption may lead to health benefits, and reformulation of bakery products may be a strategy to globally improve the diet., Objectives: This study aimed to assess the impact of a 2-wk breakfast consumption with a sourdough-leavened croissant containing a blend of dietary fiber from 10 sources (4.8 g/100 g, croissant enriched with dietary fibers [FIBCRO]), compared with a control croissant (dietary fibers 1.3 g/100 g, CONCRO) on daily energy intake, appetite, metabolic variables, and the gut microbiome., Methods: Thirty-two healthy participants were randomly allocated to 2 groups consuming FIBCRO or CONCRO. Participants self-recorded their diet and appetite through 7-d weighted food diaries and visual analog scales every day over the 2 wk. At baseline and after the intervention, fasting blood and urine samples, and fecal samples were collected beside blood pressure, anthropometry, and body composition. Serum glucose, lipids, C-reactive protein, and insulin according to the official methods and serum dipeptidyl peptidase-4 (DPPIV) activity by photometric method were measured. Polyphenols and urolithins in urines were analyzed by Liquid chromatography-tandem mass spectrometry (LC/MS/MS), whereas gut microbiome in feces by shotgun metagenomics., Results: FIBCRO consumption improved fasting blood glucose compared with CONCRO (mean changes from baseline -2.0 mg/dL in FIBCRO compared with +3.1 mg/dL in CONCRO, P = 0.022), also reducing serum DPPIV activity by 1.7 IU/L (P = 0.01) and increasing urinary excretion of urolithin A-sulfate by 6.9 ng/mg creatinine (P = 0.04) compared with baseline. No further changes in any of the monitored variables or in the gut microbiome were detected., Conclusions: Results suggested that a 2-wk consumption of a sourdough croissant claimed as "source of dietary fiber" improved fasting glycemia compared with a conventional sourdough croissant in healthy subjects. The reduced serum DPPIV activity and increased bioavailability of urolithin likely contributed to determine that effect independently from gut microbiome changes. This trial was registered at clinicaltrials.gov as NCT04999280., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Ellagic acid (EA) is a dietary polyphenol that widely exists in grapes, strawberries, and walnuts. It usually exerts multiple biological activities together with its in vivo metabolites called urolithins. EA and urolithins had been proposed as natural agents for applying on the early intervention of Alzheimer’s disease (AD). However, the neuroprotective effects of those small molecules have not been confirmed, and the action mechanism is not clear. Deposition of beta-amyloid (Aβ) protein is well documented as being involved in the initiation and pathological process of AD. In the present study, we investigated the attenuating effects of EA and several urolithins on Aβ25–35-induced neuronal injury and its underlying molecular mechanism by constructing the in vitro AD cell model of PC12 cells and primary neurons. The results revealed that EA and urolithins especially the UM5 and UM6 exerted promising neuroprotective effects in improving the Aβ25–35-induced cell damage and lactate dehydrogenase (LDH) leakage, reducing reactive oxygen species (ROS) production, inhibiting neuronal apoptosis, and promoting neurite outgrowth. These results provide new insights into the development of UM5 and UM6 as anti-AD candidates. A network pharmacology analysis combining molecular docking strategy was further adopted to predict the signaling pathway involved in the anti-AD action of EA and urolithins, and the activation of PI3K-Akt, as well as the inhibition of MAPK was found to be involved.

Atherosclerotic cardiovascular disease (ACVD) is the leading cause of death worldwide. Although current therapies, such as statins, have led to a marked reduction in morbidity and mortality from ACVD, they are associated with considerable residual risk for the disease together with various adverse side effects. Natural compounds are generally well-tolerated; a major recent goal has been to harness their full potential in the prevention and treatment of ACVD, either alone or together with existing pharmacotherapies. Punicalagin (PC) is the main polyphenol present in pomegranates and pomegranate juice and demonstrates many beneficial actions, including anti-inflammatory, antioxidant, and anti-atherogenic properties. The objective of this review is to inform on our current understanding of the pathogenesis of ACVD and the potential mechanisms underlying the beneficial actions of PC and its metabolites in the disease, including the attenuation of dyslipidemia, oxidative stress, endothelial cell dysfunction, foam cell formation, and inflammation mediated by cytokines and immune cells together with the regulation of proliferation and migration of vascular smooth muscle cells. Some of the anti-inflammatory and antioxidant properties of PC and its metabolites are due to their strong radical-scavenging activities. PC and its metabolites also inhibit the risk factors of atherosclerosis, including hyperlipidemia, diabetes mellitus, inflammation, hypertension, obesity, and non-alcoholic fatty liver disease. Despite the promising findings that have emerged from numerous in vitro, in vivo, and clinical studies, deeper mechanistic insights and large clinical trials are required to harness the full potential of PC and its metabolites in the prevention and treatment of ACVD.

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Metabolites produced by the gut microbiota have been shown to play an important role in numerous inflammatory, neuropsychiatric, and neurodegenerative diseases. Specifically, microbial metabolites have been implicated in the modulation of innate and adaptive immunity, especially in the generation of regulatory T cells (Tregs), which are key regulators of multiple sclerosis (MS) pathogenesis. Furthermore, they affect processes relevant to MS pathophysiology, such as inflammation and demyelination, which makes them attractive molecules to be explored as therapeutics in MS. In this review, we discuss the importance of these metabolites as factors contributing to disease pathogenesis and as therapeutic targets in MS. Establishing an improved understanding of these gut-microbiota derived metabolites may provide new avenues for the treatment of MS. [ABSTRACT FROM AUTHOR]

Reactive oxygen and carbonyl species promote oxidative and carbonyl stress, and the development of diabetes, metabolic syndrome, cardiovascular diseases, and others. The traditional herb Cistus × incanus is known for its antioxidant properties; therefore, the current study aimed to assess how the chemical composition of a C. incanus water infusion corresponds with its antioxidative and antiglycative effects in vitro. The composition of infusions prepared from commercial products was analyzed with UHPLC-ESI-qTOF-MS. Total phenolics, flavonoids, and non-flavonoid polyphenols were determined. Antioxidant activity of infusions and selected polyphenols was investigated using DPPH, ABTS, and FRAP. Fluorometric measurements and methylglyoxal capture were performed to investigate the antiglycation activity. PCA and PLS-DA models were applied to explore the correlation between chemical and antioxidant results. The principal flavonoids in C. incanus were flavonols. In vitro tests revealed that a stronger antioxidant effect was demonstrated by plant material from Turkey rich in flavonoids, followed by Albania and Greece. Flavonols and ellagic acid displayed stronger antiradical and reducing power than EA-derived urolithins. Hyperoside was the most potent inhibitor of glycation. The results indicate that flavonoids are primarily responsible for rock rose antioxidant and antiglycation properties. PLS-DA modeling can be used to identify the origin of plant material with sensitivity and specificity exceeding 86%. [ABSTRACT FROM AUTHOR]

Metabolites produced by the gut microbiota have been shown to play an important role in numerous inflammatory, neuropsychiatric, and neurodegenerative diseases. Specifically, microbial metabolites have been implicated in the modulation of innate and adaptive immunity, especially in the generation of regulatory T cells (Tregs), which are key regulators of multiple sclerosis (MS) pathogenesis. Furthermore, they affect processes relevant to MS pathophysiology, such as inflammation and demyelination, which makes them attractive molecules to be explored as therapeutics in MS. In this review, we discuss the importance of these metabolites as factors contributing to disease pathogenesis and as therapeutic targets in MS. Establishing an improved understanding of these gut-microbiota derived metabolites may provide new avenues for the treatment of MS.

Flavonoids are a biodiverse family of dietary compounds that have antioxidant, anti-inflammatory, antiviral, and antibacterial cell protective profiles. They have received considerable attention as potential therapeutic agents in biomedicine and have been widely used in traditional complimentary medicine for generations. Such complimentary medical herbal formulations are extremely complex mixtures of many pharmacologically active compounds that provide a therapeutic outcome through a network pharmacological effects of considerable complexity. Methods are emerging to determine the active components used in complimentary medicine and their therapeutic targets and to decipher the complexities of how network pharmacology provides such therapeutic effects. The gut microbiome has important roles to play in the generation of bioactive flavonoid metabolites retaining or exceeding the antioxidative and anti-inflammatory properties of the intact flavonoid and, in some cases, new antitumor and antineurodegenerative bioactivities. Certain food items have been identified with high prebiotic profiles suggesting that neutraceutical supplementation may be beneficially employed to preserve a healthy population of bacterial symbiont species and minimize the establishment of harmful pathogenic organisms. Gut health is an important consideration effecting the overall health and wellbeing of linked organ systems. Bioconversion of dietary flavonoid components in the gut generates therapeutic metabolites that can also be transported by the vagus nerve and systemic circulation to brain cell populations to exert a beneficial effect. This is particularly important in a number of neurological disorders (autism, bipolar disorder, AD, PD) characterized by effects on moods, resulting in depression and anxiety, impaired motor function, and long-term cognitive decline. Native flavonoids have many beneficial properties in the alleviation of inflammation in tissues, however, concerns have been raised that therapeutic levels of flavonoids may not be achieved, thus allowing them to display optimal therapeutic effects. Dietary manipulation and vagal stimulation have both yielded beneficial responses in the treatment of autism spectrum disorders, depression, and anxiety, establishing the vagal nerve as a route of communication in the gut-brain axis with established roles in disease intervention. While a number of native flavonoids are beneficial in the treatment of neurological disorders and are known to penetrate the blood–brain barrier, microbiome-generated flavonoid metabolites (e.g., protocatechuic acid, urolithins, γ-valerolactones), which retain the antioxidant and anti-inflammatory potency of the native flavonoid in addition to bioactive properties that promote mitochondrial health and cerebrovascular microcapillary function, should also be considered as potential biotherapeutic agents. Studies are warranted to experimentally examine the efficacy of flavonoid metabolites directly, as they emerge as novel therapeutic options.

In this work, quantum chemical calculations based on density functional theory (DFT) were performed to predict the antioxidant potential of four bioactive gut microbiota metabolites of the natural polyphenols ellagitannins (ETs) and ellagic acid (EA), also known as urolithins (UROs). In order to evaluate their ability to counter the effect of oxidative stress caused by reactive oxygen species (ROS), such as the hydroperoxyl radical (•OOH), different reaction mechanisms were investigated, considering water and lipid-like environments. Through our in silico results, it emerged that at physiological pH, the scavenging activity of all urolithins, except urolithin B, are higher than that of trolox and other potent antioxidants existing in nature, such as EA, α-mangostin, allicin, caffeine and melatonin. These findings were confirmed by experimental assays.

Liver pyruvate kinase (PKL) has recently emerged as a new target for non-alcoholic fatty liver disease (NAFLD), and inhibitors of this enzyme could represent a new therapeutic option. However, this breakthrough is complicated by selectivity issues since pyruvate kinase exists in four different isoforms. In this work, we report that ellagic acid (EA) and its derivatives, present in numerous fruits and vegetables, can inhibit PKL potently and selectively. Several polyphenolic analogues of EA were synthesized and tested to identify the chemical features responsible for the desired activity. Molecular modelling studies suggested that this inhibition is related to the stabilization of the PKL inactive state. This unique inhibition mechanism could potentially herald the development of new therapeutics for NAFLD.

Ellagitannins (ETs) are a large group of bioactive compounds found in plant-source foods, such as pomegranates, berries, and nuts. The consumption of ETs has often been associated with positive effects on many pathologies, including cardiovascular diseases, neurodegenerative syndromes, and cancer. Although multiple biological activities (antioxidant, anti-inflammatory, chemopreventive) have been discussed for ETs, their limited bioavailability prevents reaching significant concentrations in systemic circulation. Instead, urolithins, ET gut microbiota-derived metabolites, are better absorbed and could be the bioactive molecules responsible for the antioxidant and anti-inflammatory activities or anti-tumor cell progression. In this review, we examined the dietary sources, metabolism, and bioavailability of ETs, and analyzed the last recent findings on ETs, ellagic acid, and urolithins, their intestinal and brain activities, the potential mechanisms of action, and the connection between the ET microbiota metabolism and the consequences detected on the gut–brain axis. The current in vitro, in vivo, and clinical studies indicate that ET-rich foods, individual gut microbiomes, or urolithin types could modulate signaling pathways and promote beneficial health effects. A better understanding of the role of these metabolites in disease pathogenesis may assist in the prevention or treatment of pathologies targeting the gut–brain axis.

The increasing prevalence of diabetic kidney disease (DKD), a common complication of type 1 and type 2 diabetes, is becoming a leading risk factor of developing end stage renal disease (ESRD). The multiple mechanisms involved in renal tissue damage are a challenge for effective targeted therapy. Urolithins are metabolites generated by gut microbiota upon dietary intake of plant-derived ellagitannins. Multidirectional effects of these compounds include their anti-inflammatory, antioxidant, anti-proliferatory, anti-migratory and antiglycative properties that are mediated by modulation of signaling pathways and gene expression. Biochemical properties of urolithins indicate their capacity to regulate numerous mechanisms responsible for developing the hyperglycemia-induced tissue injury. The potentially beneficial effects of urolithins on podocytes, the most vulnerable renal cells should be particularly considered. The purpose of this review is to provide the evidence from the in vivo and in vitro studies showing that urolithin-based therapy could be a useful tool for protecting the kidneys from damage in diabetes. [ABSTRACT FROM AUTHOR]

Abstract Polyphenols are plant‐derived natural compounds, which are attributed to various beneficial effects on human health. Therefore, they are extensively investigated in different experimental setups. These compounds exhibit favorable antidiabetic effects in various clinical trials. However, their mode of action is not completely elucidated. A potential molecular target of certain polyphenols could be the dipeptidyl peptidase IV (DPP IV). This enzyme is abundant in human serum and represents a serine exopeptidase that cleaves and thus rapidly deactivates incretin hormones which are responsible for adequate postprandial insulin secretion from the pancreas. Multiple inhibitors of DPP IV have already been approved as antidiabetic drugs. In the course of screening assays exploring in vitro DPP IV inhibitory activities of polyphenols, some implausible observations prompted a detailed analysis of the interaction of polyphenols with fluorescence signals. The results revealed that quercetin quenched the fluorescence intensity, while 6‐methoxyflavone and urolithin B enhanced fluorescence signals depending on particular experimental conditions such as solvent composition. Thus, individual polyphenols might conflict with the experimental setup of fluorescence‐based DPP IV inhibitor screening assays. To avoid false positive or false negative results, polyphenols under investigations should be carefully controlled for potential assay interferences.

Summary: Raspberry leaves, by‐products in raspberry production, are also a rich source of bioactive phytochemicals. In this study, the changes of phenolic compounds in raspberries leaf extract (RLE) under in vitro digestion and colonic fermentation were further studied by HPLC‐MS analysis and 16S rRNA. The results showed that the phenolic compounds in RLE were relatively stable during in vitro gastric digestion; however, in the subsequent intestinal digestion and colonic fermentation, their content decreased sharply. A large amount of hydroxyphenylpropionic acid, hydroxyphenylacetic acid and urolithins were produced under the action of gut microbiota. Moreover, compared with corresponding control, RLE significantly reduced the ratio of Firmicutes/Bacteroidetes in all volunteers, increased the relative abundances of some beneficial bacteria, Enterococcus, Prevotella, and decreased the relative abundances of potential pathogens, Clostridium and Faecalibacterium. These findings suggest that RLE during in vitro digestion and fermentation has positive effects on gut microbiota and potential value of maintaining intestinal health. [ABSTRACT FROM AUTHOR]

Abdulrasheed O Abdulrahman,1 Abudukadeer Kuerban,1 Zuhair Ahmed Alshehri,1 Wesam H Abdulaal,1 Jalaluddin Awlia Khan,1 Mohammad Imran Khan1,2 1Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia; 2Cancer Metabolism and Epigenetic Unit, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi ArabiaCorrespondence: Mohammad Imran KhanDepartment of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi ArabiaTel +966-12-6952000Email mikhan@kau.edu.saBackground: Urolithins are gut microbiota-derived polyphenol metabolites, produced following the consumption of pomegranate, berries, and nuts. Recent studies have shown the potentials of these metabolites on reducing triglycerides accumulation in cultured hepatocytes and adipocytes. In this study, we investigated the ability of both urolithin A (Uro-A) and urolithin B (Uro-B) to attenuate obesity and associated symptoms in a high-fat diet-induced obesity model in rats.Methods: Twenty-four male Wistar rats were randomly assigned to four groups. Group 1 was fed on a normal diet while groups 2, 3, and 4 were fed on a high-fat diet for 10 weeks. After this, groups 3 and 4 were treated with 2.5mg/kg body weight of Uro-A and Uro-B intraperitoneally, respectively. Body weight, serum lipid profile, hepatic antioxidant activity, hepatic lipid accumulation, fecal lipid content, and the expressions of genes involved in lipogenesis and hepatic ER stress were quantified.Results: Indeed, a high-fat diet resulted in increased body weight, visceral adipose tissue mass, and oxidative stress in rats. However, treatment with both Uro-A and Uro-B decreased body weight and visceral adipose tissue mass. These metabolites restored hepatic antioxidant capacity and decreased lipid accumulation in addition to an increase in fecal fat excretion. Moreover, both Uro-A and Uro-B treatment downregulated the expression of LXRα and SREBP1c; involved in de novo lipogenesis while upregulating PPARα expression for increased fatty acid oxidation. Furthermore, Uro-A and Uro-B decreased the expression of PERK and IRE1α; which are involved in hepatic ER stress. Taken together, our results showed the potentials of Uro-A and Uro-B in mitigating obesity symptoms and they could thus provide promising roles in the future as functional anti-obesity candidates.Keywords: de novo lipogenesis, ER stress, high-fat diet, obesity, pomegranate, urolithins

Fireweed (Epilobium angustifolium L.) is a well-known medicinal plant traditionally used in the treatment of urogenital diseases, stomach and liver disorders, skin problems, etc. E. angustifolium extracts show anti-androgenic, antiproliferative, cytotoxic, antioxidant, anti-inflammatory, immunomodulatory, and antimicrobial activities. The unique combination of biological properties demonstrated by the results of some studies indicates that fireweed has a positive effect in benign prostatic hyperplasia (BPH) and potentially in the prostate cancer chemoprevention. However, the efficacy of E. angustifolium phytotherapy is still poorly tested in clinical trials, while numerous beneficial effects of extracts have been documented in the in vitro and in vivo tests. Fireweed is rich in polyphenolic compounds, particularly ellagitannins. Currently, polyphenols are considered to be modulators of beneficial gut microbiota. The literature data support the use of ellagitannins in the prostate cancer chemoprevention, but caution is advised due to the highly variable production of urolithins by the individual microbiota. A better understanding of the microbiota’s role and the mechanisms of its action are crucial for an optimal therapeutic effect. This paper aims to summarize and discuss experimental data concerning pharmacological properties of E. angustifolium and bioavailability of ellagitannins – important bioactive compounds of this plant.

The pericarp extract of Trapa bispinosa (TBPE), which is rich in hydrolyzable tannins, has been reported to inhibit α-glucosidase and glycation reactions. We investigated the in vivo behavior of hydrolyzable tannins and related metabolites after administration of TBPE to rats. Using high pressure liquid chromatography-electrospray ionization-tandem mass spectroscopy (HPLC-ESI-MS/MS), 12 ellagitannin metabolites, such as urolithins and 6 gallotannin metabolites, produced in the collected plasma and urine were quantified. Urolithins and gallic acid metabolites reached their maximum blood concentration after 24 and 1 h of administration, respectively. Conversely, the excretion of urolithins in urine required up to 72 h and followed a sigmoidal curve, whereas gallic acid metabolites were rapidly excreted earlier after administration. The results suggest that the metabolites gallotannin and ellagitannin are responsible for the antiglycation effect of TBPE, which proceeds via different mechanisms and times. Our findings provide basic data demonstrating the functionality of hydrolyzable tannins as well as Trapa ingredients.

Urolithins are bioactive compounds generated in human and animal intestines because of the bacterial metabolism of dietary ellagitannins (and their constituent, ellagic acid). Due to their multidirectional effects, including anti-inflammatory, antioxidant, anti-cancer, neuroprotective, and antiglycative properties, urolithins are potential novel therapeutic agents. In this study, while considering the future possibility of using urolithins to improve podocyte function in diabetes, we assessed the results of exposing mouse podocytes cultured in normal (NG, 5.5 mM) and high (HG, 25 mM) glucose concentrations to urolithin A (UA) and urolithin B (UB). Podocytes metabolized UA to form glucuronides in a time-dependent manner; however, in HG conditions, the metabolism was lower than in NG conditions. In HG milieu, UA improved podocyte viability more efficiently than UB and reduced the reactive oxygen species level. Both types of urolithins showed cytotoxic activity at high (100 µM) concentration. The UA upregulated total and surface nephrin expression, which was paralleled by enhanced nephrin internalization. Regulation of nephrin turnover was independent of ambient glucose concentration. We conclude that UA affects podocytes in different metabolic and functional aspects. With respect to its pro-survival effects in HG-induced toxicity, UA could be considered as a potent therapeutic candidate against diabetic podocytopathy.

Cancer as a disease continues to ravage the world population without regard to sex, age, and race. Due to the growing number of cases worldwide, cancer exerts a significant negative impact on global health and the economy. Interestingly, chemotherapy has been used over the years as a therapeutic intervention against cancer. However, high cost, resistance, and toxic by-effects to treatment have overshadowed some of its benefits. In recent times, efforts have been ongoing in searching for anticancer therapeutics of plant origin, focusing on polyphenols. Urolithins are secondary polyphenol metabolites derived from the gut microbial action on ellagitannins and ellagic acid-rich foods such as pomegranate, berries, and nuts. Urolithins are emerging as a new class of anticancer compounds that can mediate their cancer-preventive activities through cell cycle arrest, aromatase inhibition, induction of apoptosis, tumor suppression, promotion of autophagy, and senescence, transcriptional regulation of oncogenes, and growth factor receptors. In this review, we discussed the growing shreds of evidence supporting these secondary phenolic metabolites' anticancer properties. Furthermore, we have pointed out some of the future directions needed to establish urolithins as anticancer agents.