Effects of Urolithin A on Mitochondrial Parameters in a Cellular Model of Early Alzheimer Disease
Int J Mol Sci. 2021 Aug 3;22(15):8333.
Background: Ellagitannins are natural products occurring in pomegranate and walnuts. They are hydrolyzed in the gut to release ellagic acid, which is further metabolized by the microflora into urolithins, such as urolithin A (UA). Accumulation of damaged mitochondria is a hallmark of aging and age-related neurodegenerative diseases. In this study, we investigated the neuroprotective activity of the metabolite UA against mitochondrial dysfunction in a cellular model of early Alzheimer disease (AD).
Methods: In the present study we used SH-SY5Y-APP695 cells and its corresponding controls (SH-SY5Ymock) to assess UA's effect on mitochondrial function. Using these cells we investigated mitochondrial respiration (OXPHOS), mitochondrial membrane potential (MMP), adenosine triphosphate (ATP) production, autophagy and levels of reactive oxygen species (ROS) in cells treated with UA. Furthermore, we assessed UA's effect on the expression of genes related to mitochondrial bioenergetics, mitochondrial biogenesis, and autophagy via quantitative real-time PCR (qRT-PCR).
Results: Treatment of SH-SY5Y-APP695 cells suggests changes to autophagy corresponding with qRT-PCR results. However, LC3B-I, LC3B-II, and p62 levels were unchanged. UA (10 µM) reduced MMP, and ATP-levels. Treatment of cells with UA (1 µM) for 24 h did not affect ROS production or levels of Aβ, but significantly increased expression of genes for mitochondrial biogenesis and OXPHOS. Mitochondrial Transcription Factor A (TFAM) expression was specifically increased in SH-SY5Y-APP695. Both cell lines showed unaltered levels of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), which is commonly associated with mitochondrial biogenesis. Results imply that biogenesis might be facilitated by estrogen-related receptor (ESRR) genes.
Conclusion: Urolithin A shows no effect on autophagy in SH-SY5Y-APP695 cells and its effect on mitochondrial function is limited. Instead, data suggests that UA treatment induces metaphoric effects as it induces transcription of several genes related to mitochondrial biogenesis.
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Urolithin A
Re: Urolithin A
Impact of the Natural Compound Urolithin A on Health, Disease, and Aging
Trends Mol Med. 2021 Jul;27(7):687-699.
Urolithin A (UA) is a natural compound produced by gut bacteria from ingested ellagitannins (ETs) and ellagic acid (EA), complex polyphenols abundant in foods such as pomegranate, berries, and nuts. UA was discovered 40 years ago, but only recently has its impact on aging and disease been explored. UA enhances cellular health by increasing mitophagy and mitochondrial function and reducing detrimental inflammation. Several preclinical studies show how UA protects against aging and age-related conditions affecting muscle, brain, joints, and other organs. In humans, benefits of UA supplementation in the muscle are supported by recent clinical trials in elderly people. Here, we review the state of the art of UA's biology and its translational potential as a nutritional intervention in humans.
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Trends Mol Med. 2021 Jul;27(7):687-699.
Urolithin A (UA) is a natural compound produced by gut bacteria from ingested ellagitannins (ETs) and ellagic acid (EA), complex polyphenols abundant in foods such as pomegranate, berries, and nuts. UA was discovered 40 years ago, but only recently has its impact on aging and disease been explored. UA enhances cellular health by increasing mitophagy and mitochondrial function and reducing detrimental inflammation. Several preclinical studies show how UA protects against aging and age-related conditions affecting muscle, brain, joints, and other organs. In humans, benefits of UA supplementation in the muscle are supported by recent clinical trials in elderly people. Here, we review the state of the art of UA's biology and its translational potential as a nutritional intervention in humans.
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Re: Urolithin A
Differential Effects of Whole Red Raspberry Polyphenols and Their Gut Metabolite Urolithin A on Neuroinflammation in BV-2 Microglia
Int J Environ Res Public Health. 2020 Dec 24;18(1):68.
Whole red raspberry polyphenols (RRW), including ellagic acid, and their gut-derived metabolite, urolithin A (UroA), attenuate inflammation and confer health benefits. Although results from recent studies indicate that polyphenols and UroA also provide neuroprotective effects, these compounds differ in their bioavailability and may, therefore, have unique effects on limiting neuroinflammation. Accordingly, we aimed to compare the neuroprotective effects of RRW and UroA on BV-2 microglia under both 3 h and 12 and 24 h inflammatory conditions. In inflammation induced by lipopolysaccharide (LPS) and ATP stimulation after 3 h, RRW and UroA suppressed pro-inflammatory cytokine gene expression and regulated the JNK/c-Jun signaling pathway. UroA also reduced inducible nitric oxide synthase gene expression and promoted M2 microglial polarization. During inflammatory conditions induced by either 12 or 24 h stimulation with LPS, UroA-but not RRW-dampened pro-inflammatory cytokine gene expression and suppressed JNK/c-Jun signaling. Taken together, these results demonstrate that RRW and its gut-derived metabolite UroA differentially regulate neuroprotective responses in microglia during 3 h versus 12 and 24 h inflammatory conditions.
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Int J Environ Res Public Health. 2020 Dec 24;18(1):68.
Whole red raspberry polyphenols (RRW), including ellagic acid, and their gut-derived metabolite, urolithin A (UroA), attenuate inflammation and confer health benefits. Although results from recent studies indicate that polyphenols and UroA also provide neuroprotective effects, these compounds differ in their bioavailability and may, therefore, have unique effects on limiting neuroinflammation. Accordingly, we aimed to compare the neuroprotective effects of RRW and UroA on BV-2 microglia under both 3 h and 12 and 24 h inflammatory conditions. In inflammation induced by lipopolysaccharide (LPS) and ATP stimulation after 3 h, RRW and UroA suppressed pro-inflammatory cytokine gene expression and regulated the JNK/c-Jun signaling pathway. UroA also reduced inducible nitric oxide synthase gene expression and promoted M2 microglial polarization. During inflammatory conditions induced by either 12 or 24 h stimulation with LPS, UroA-but not RRW-dampened pro-inflammatory cytokine gene expression and suppressed JNK/c-Jun signaling. Taken together, these results demonstrate that RRW and its gut-derived metabolite UroA differentially regulate neuroprotective responses in microglia during 3 h versus 12 and 24 h inflammatory conditions.
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Urolithin A ameliorates experimental autoimmune encephalomyelitis by targeting aryl hydrocarbon receptor
EBioMedicine. 2021 Feb;64:103227.
Background: Urolithin A (URA) is an intestinal microbiota metabolic product from ellagitannin-containing foods with multiple biological activities. However, its role in autoimmune diseases is largely unknown. Here, for first time, we demonstrate the therapeutic effect of URA in an experimental autoimmune encephalomyelitis (EAE) animal model.
Methods: Therapeutic effect was evaluated via an active and passive EAE animal model in vivo. The function of URA on bone marrow-derived dendritic cells (BM-DCs), T cells, and microglia were tested in vitro.
Findings: Oral URA (25 mg/kg/d) suppressed disease progression at prevention, induction, and effector phases of preclinical EAE. Histological evaluation showed that significantly fewer inflammatory cells, decreased demyelination, lower numbers of M1-type microglia and activated DCs, as well as reduced infiltrating Th1/Th17 cells were present in the central nervous system (CNS) of the URA-treated group. URA treatment at 25 μM inhibited the activation of BM-DCs in vitro, restrained Th17 cell differentiation in T cell polarization conditions, and in a DC-CD4+ T cell co-culture system. Moreover, we confirmed URA inhibited pathogenicity of Th17 cells in adoptive EAE. Mechanism of URA action was directly targeting Aryl Hydrocarbon Receptor (AhR) and modulating the signaling pathways.
Interpretation: Collectively, our study offers new evidence that URA, as a human microbial metabolite, is valuable to use as a prospective therapeutic candidate for autoimmune diseases.
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EBioMedicine. 2021 Feb;64:103227.
Background: Urolithin A (URA) is an intestinal microbiota metabolic product from ellagitannin-containing foods with multiple biological activities. However, its role in autoimmune diseases is largely unknown. Here, for first time, we demonstrate the therapeutic effect of URA in an experimental autoimmune encephalomyelitis (EAE) animal model.
Methods: Therapeutic effect was evaluated via an active and passive EAE animal model in vivo. The function of URA on bone marrow-derived dendritic cells (BM-DCs), T cells, and microglia were tested in vitro.
Findings: Oral URA (25 mg/kg/d) suppressed disease progression at prevention, induction, and effector phases of preclinical EAE. Histological evaluation showed that significantly fewer inflammatory cells, decreased demyelination, lower numbers of M1-type microglia and activated DCs, as well as reduced infiltrating Th1/Th17 cells were present in the central nervous system (CNS) of the URA-treated group. URA treatment at 25 μM inhibited the activation of BM-DCs in vitro, restrained Th17 cell differentiation in T cell polarization conditions, and in a DC-CD4+ T cell co-culture system. Moreover, we confirmed URA inhibited pathogenicity of Th17 cells in adoptive EAE. Mechanism of URA action was directly targeting Aryl Hydrocarbon Receptor (AhR) and modulating the signaling pathways.
Interpretation: Collectively, our study offers new evidence that URA, as a human microbial metabolite, is valuable to use as a prospective therapeutic candidate for autoimmune diseases.
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Re: Urolithin A
The Metabolite Urolithin-A Ameliorates Oxidative Stress in Neuro-2a Cells, Becoming a Potential Neuroprotective Agent
Antioxidants (Basel). 2020 Feb 21;9(2):177.
Urolithin A is a metabolite generated from ellagic acid and ellagitannins by the intestinal microbiota after consumption of fruits such as pomegranates or strawberries. The objective of this study was to determine the cytoprotective capacity of this polyphenol in Neuro-2a cells subjected to oxidative stress, as well as its direct radical scavenging activity and properties as an inhibitor of oxidases. Cells treated with this compound and H2O2 showed a greater response to oxidative stress than cells only treated with H2O2, as mitochondrial activity (MTT assay), redox state (ROS formation, lipid peroxidation), and the activity of antioxidant enzymes (CAT: catalase, SOD: superoxide dismutase, GR: glutathione reductase, GPx: glutathione peroxidase) were significantly ameliorated; additionally, urolithin A enhanced the expression of cytoprotective peroxiredoxins 1 and 3. Urolithin A also acted as a direct radical scavenger, showing values of 13.2 μM Trolox Equivalents for Oxygen Radical Absorbance Capacity (ORAC) and 5.01 µM and 152.66 µM IC50 values for superoxide and 2,2-diphenyss1-picrylhydrazyl (DPPH) radicals, respectively. Finally, inhibition of oxidizing enzymes, such as monoamine oxidase A and tyrosinase, was also detected in a dose-dependent manner. The cytoprotective effects of urolithin A could be attributed to the improvement of the cellular antioxidant battery, but also to its role as a direct radical scavenger and enzyme inhibitor of oxidases.
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Antioxidants (Basel). 2020 Feb 21;9(2):177.
Urolithin A is a metabolite generated from ellagic acid and ellagitannins by the intestinal microbiota after consumption of fruits such as pomegranates or strawberries. The objective of this study was to determine the cytoprotective capacity of this polyphenol in Neuro-2a cells subjected to oxidative stress, as well as its direct radical scavenging activity and properties as an inhibitor of oxidases. Cells treated with this compound and H2O2 showed a greater response to oxidative stress than cells only treated with H2O2, as mitochondrial activity (MTT assay), redox state (ROS formation, lipid peroxidation), and the activity of antioxidant enzymes (CAT: catalase, SOD: superoxide dismutase, GR: glutathione reductase, GPx: glutathione peroxidase) were significantly ameliorated; additionally, urolithin A enhanced the expression of cytoprotective peroxiredoxins 1 and 3. Urolithin A also acted as a direct radical scavenger, showing values of 13.2 μM Trolox Equivalents for Oxygen Radical Absorbance Capacity (ORAC) and 5.01 µM and 152.66 µM IC50 values for superoxide and 2,2-diphenyss1-picrylhydrazyl (DPPH) radicals, respectively. Finally, inhibition of oxidizing enzymes, such as monoamine oxidase A and tyrosinase, was also detected in a dose-dependent manner. The cytoprotective effects of urolithin A could be attributed to the improvement of the cellular antioxidant battery, but also to its role as a direct radical scavenger and enzyme inhibitor of oxidases.
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Coumarins as Modulators of the Keap1/Nrf2/ARE Signaling Pathway
Oxid Med Cell Longev. 2020 Apr 22;2020:1675957.
The Keap1/Nrf2/ARE system is a central defensive mechanism against oxidative stress which plays a key role in the pathogenesis and progression of many diseases. Nrf2 is a redox-sensitive transcription factor controlling a variety of downstream antioxidant and cytodefensive genes. Nrf2 has a powerful anti-inflammatory activity mediated via modulating NF-κB. Therefore, pharmacological activation of Nrf2 is a promising therapeutic strategy for the treatment/prevention of several diseases that are underlined by both oxidative stress and inflammation. Coumarins are natural products with promising pharmacological activities, including antioxidant, anticancer, antimicrobial, and anti-inflammatory efficacies. Coumarins are found in many plants, fungi, and bacteria and have been widely used as complementary and alternative medicines. Some coumarins have shown an ability to activate Nrf2 signaling in different cells and animal models. The present review compiles the research findings of seventeen coumarin derivatives of plant origin (imperatorin, visnagin, urolithin B, urolithin A, scopoletin, esculin, esculetin, umbelliferone, fraxetin, fraxin, daphnetin, anomalin, wedelolactone, glycycoumarin, osthole, hydrangenol, and isoimperatorin) as antioxidant and anti-inflammatory agents, emphasizing the role of Nrf2 activation in their pharmacological activities. Additionally, molecular docking simulations were utilized to investigate the potential binding mode of these coumarins with Keap1 as a strategy to disrupt Keap1/Nrf2 protein-protein interaction and activate Nrf2 signaling.
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Oxid Med Cell Longev. 2020 Apr 22;2020:1675957.
The Keap1/Nrf2/ARE system is a central defensive mechanism against oxidative stress which plays a key role in the pathogenesis and progression of many diseases. Nrf2 is a redox-sensitive transcription factor controlling a variety of downstream antioxidant and cytodefensive genes. Nrf2 has a powerful anti-inflammatory activity mediated via modulating NF-κB. Therefore, pharmacological activation of Nrf2 is a promising therapeutic strategy for the treatment/prevention of several diseases that are underlined by both oxidative stress and inflammation. Coumarins are natural products with promising pharmacological activities, including antioxidant, anticancer, antimicrobial, and anti-inflammatory efficacies. Coumarins are found in many plants, fungi, and bacteria and have been widely used as complementary and alternative medicines. Some coumarins have shown an ability to activate Nrf2 signaling in different cells and animal models. The present review compiles the research findings of seventeen coumarin derivatives of plant origin (imperatorin, visnagin, urolithin B, urolithin A, scopoletin, esculin, esculetin, umbelliferone, fraxetin, fraxin, daphnetin, anomalin, wedelolactone, glycycoumarin, osthole, hydrangenol, and isoimperatorin) as antioxidant and anti-inflammatory agents, emphasizing the role of Nrf2 activation in their pharmacological activities. Additionally, molecular docking simulations were utilized to investigate the potential binding mode of these coumarins with Keap1 as a strategy to disrupt Keap1/Nrf2 protein-protein interaction and activate Nrf2 signaling.
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