3-8-dihydroxy-6h-dibenzo(b-d)pyran-6-one and Disease-Models--Animal

Mitochondrial dysfunction contributes to the pathogenesis of neurodegenerative diseases such as Parkinson's disease (PD). Therapeutic strategies targeting mitochondrial dysfunction hold considerable promise for the treatment of PD. Recent reports have highlighted the protective role of urolithin A (UA), a gut metabolite produced from ellagic acid-containing foods such as pomegranates, berries and walnuts, in several neurological disorders including Alzheimer's disease and ischemic stroke. However, the potential role of UA in PD has not been characterized. In this study, we investigated the underlying mechanisms for role of UA in 6-OHDA-induced neurotoxicity in cell cultures and mice model of PD. Our results revealed that UA protected against 6-OHDA cytotoxicity and apoptosis in PC12 cells. Meanwhile, administration of UA to 6-OHDA lesioned mice ameliorated both motor deficits and nigral-striatal dopaminergic neurotoxicity. More important, UA treatment significantly attenuated 6-OHDA-induced mitochondrial dysfunction in PC12 cells accompanied by enhanced mitochondrial biogenesis. Mechanistically, we demonstrated that UA exerts neuroprotective effects by promoting mitochondrial biogenesis

Topics: Animals; Coumarins; Disease Models, Animal; Dopaminergic Neurons; Male; Mice; Mice, Inbred C57BL; Mitochondria; Neuroprotective Agents; Parkinson Disease; PC12 Cells; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Rats; Signal Transduction; Sirtuin 1

Microglia-mediated neuroinflammation and mitochondrial dysfunction play critical role in the pathogenic process of Parkinson's disease (PD). Mitophagy plays central role in mitochondrial quality control. Hence, regulation of microglial activation through mitophagy could be a valuable strategy in controlling microglia-mediated neurodegeneration and neuroinflammation. Urolithin A (UA) is a natural compound produced by gut bacteria from ingested ellagitannins (ETs) and ellagic acid (EA). Several preclinical studies have reported the beneficial effects of UA on age-related conditions by increasing mitophagy and blunting excessive inflammatory responses. However, the specific role of UA in pathology of PD remains unknown. In this study, we showed that treatment with UA reduced the loss of dopaminergic neurons, ameliorated behavioral deficits and neuroinflammation in MPTP mouse model of PD. Further study revealed that UA promotes mitophagy, restores mitochondrial function and attenuate proinflammatory response in BV2 microglial cells exposed to LPS. Moreover, UA also reduced NLRP3 inflammasome activation both in vitro and in vivo. Importantly, disruption of microglial mitophagy with pharmacological or genetic approach partly blunted the neuroprotective effects of UA in MPTP mouse model of PD. Collectively, these results provide strong evidence that UA protects against dopaminergic neurodegeneration and neuroinflammation. The mechanism may be related with its inhibition of NLRP3 inflammasome activation via promoting mitophagy in microglia.

Topics: Animals; Coumarins; Disease Models, Animal; Inflammasomes; Lipopolysaccharides; Mice; Mice, Inbred C57BL; Microglia; Mitochondrial Diseases; Mitophagy; MPTP Poisoning; Neuroinflammatory Diseases; Neuroprotective Agents; NLR Family, Pyrin Domain-Containing 3 Protein; Parkinson Disease

Hyperglycemia in diabetes mellitus (DM) patients is a causative factor for amyloidogenesis and induces neuropathological changes, such as impaired neuronal integrity, neurodegeneration, and cognitive impairment. Regulation of mitochondrial calcium influx from the endoplasmic reticulum (ER) is considered a promising strategy for the prevention of mitochondrial ROS (mtROS) accumulation that occurs in the Alzheimer's disease (AD)-associated pathogenesis in DM patients. Among the metabolites of ellagitannins that are produced in the gut microbiome, urolithin A has received an increasing amount of attention as a novel candidate with anti-oxidative and neuroprotective effects in AD. Here, we investigated the effect of urolithin A on high glucose-induced amyloidogenesis caused by mitochondrial calcium dysregulation and mtROS accumulation resulting in neuronal degeneration. We also identified the mechanism related to mitochondria-associated ER membrane (MAM) formation. We found that urolithin A-lowered mitochondrial calcium influx significantly alleviated high glucose-induced mtROS accumulation and expression of amyloid beta (Aβ)-producing enzymes, such as amyloid precursor protein (APP) and β-secretase-1 (BACE1), as well as Aβ production. Urolithin A injections in a streptozotocin (STZ)-induced diabetic mouse model alleviated APP and BACE1 expressions, Tau phosphorylation, Aβ deposition, and cognitive impairment. In addition, high glucose stimulated MAM formation and transglutaminase type 2 (TGM2) expression. We first discovered that urolithin A significantly reduced high glucose-induced TGM2 expression. In addition, disruption of the AIP-AhR complex was involved in urolithin A-mediated suppression of high glucose-induced TGM2 expression. Markedly, TGM2 silencing inhibited inositol 1, 4, 5-trisphosphate receptor type 1 (IP3R1)-voltage-dependent anion-selective channel protein 1 (VDAC1) interactions and prevented high glucose-induced mitochondrial calcium influx and mtROS accumulation. We also found that urolithin A or TGM2 silencing prevented Aβ-induced mitochondrial calcium influx, mtROS accumulation, Tau phosphorylation, and cell death in neuronal cells. In conclusion, we suggest that urolithin A is a promising candidate for the development of therapies to prevent DM-associated AD pathogenesis by reducing TGM2-dependent MAM formation and maintaining mitochondrial calcium and ROS homeostasis.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Calcium; Cell Line, Tumor; Coumarins; Disease Models, Animal; Endoplasmic Reticulum; Glucose; Homeostasis; Humans; Male; Mice; Mitochondria; Neurons; Protein Glutamine gamma Glutamyltransferase 2; Voltage-Dependent Anion Channel 1

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.. 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.. 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. 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.

Topics: Animals; Biomarkers; Coumarins; Disease Models, Animal; Disease Susceptibility; Encephalomyelitis, Autoimmune, Experimental; Female; Immunohistochemistry; Mice; Models, Molecular; Molecular Targeted Therapy; Receptors, Aryl Hydrocarbon; Structure-Activity Relationship

Hyperuricemia is defined as a disease with high uric acid (UA) levels in the blood and a strong risk factor for gout. Urolithin A (UroA) is a main microbial metabolite derived from ellagic acid (EA), which occurs in strawberries and pomegranates. In this study, we evaluated antihyperuricemic effect of UroA in both cultured hepatocytes and hyperuricemic model mice. In cultured hepatocytes, UroA significantly and dose-dependently reduced UA production. In model mice with purine bodies-induced hyperuricemia, oral administration of UroA significantly inhibited the increase in plasma UA levels and hepatic xanthine oxidase (XO) activity. In addition, DNA microarray results exhibited that UroA, as well as allopurinol, a strong XO inhibitor, induced downregulation of the expression of genes associated with hepatic purine metabolism. Thus, hypouricemic effect of UroA could be, at least partly, attributed to inhibition of purine metabolism and UA production by suppressing XO activity in the liver. These results indicate UroA possesses a potent antihyperuricemic effect and it could be a potential candidate for a molecule capable of preventing and improving hyperuricemia and gout.

Topics: Animals; Cell Line; Coumarins; Disease Models, Animal; Gout Suppressants; Hepatocytes; Hyperuricemia; Liver; Male; Mice; Mice, Inbred ICR; Uric Acid

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by an abnormal accumulation of amyloid-β (Aβ) plaques, neuroinflammation, and impaired neurogenesis. Urolithin A (UA), a gut-microbial metabolite of ellagic acid, has been reported to exert anti-inflammatory effects in the brain. However, it is unknown whether UA exerts its properties of anti-inflammation and neuronal protection in the APPswe/PS1ΔE9 (APP/PS1) mouse model of AD.. Morris water maze was used to detect the cognitive function. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay was performed to detect neuronal apoptosis. Immunohistochemistry analyzed the response of glia, Aβ deposition, and neurogenesis. The expression of inflammatory mediators were measured by enzyme-linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qRT-PCR). The modulating effects of UA on cell signaling pathways were assayed by Western blotting.. We demonstrated that UA ameliorated cognitive impairment, prevented neuronal apoptosis, and enhanced neurogenesis in APP/PS1 mice. Furthermore, UA attenuated Aβ deposition and peri-plaque microgliosis and astrocytosis in the cortex and hippocampus. We also found that UA affected critical cell signaling pathways, specifically by enhancing cerebral AMPK activation, decreasing the activation of P65NF-κB and P38MAPK, and suppressing Bace1 and APP degradation.. Our results indicated that UA imparted cognitive protection by protecting neurons from death and triggering neurogenesis via anti-inflammatory signaling in APP/PS1 mice, suggesting that UA might be a promising therapeutic drug to treat AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Anti-Inflammatory Agents; Brain; Coumarins; Cytokines; Disease Models, Animal; Encephalitis; Female; Gene Expression Regulation; Gliosis; Maze Learning; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nerve Tissue Proteins; Neurogenesis; Plaque, Amyloid; Presenilin-1; Signal Transduction

Cumulative kidney toxicity associated with cisplatin is severe and there is no clear consensus on the therapeutic management of the same. The pathogenesis involves activation of inflammatory and apoptotic pathways; therefore, regulating these pathways offers protection. Given the anti-inflammatory and antioxidant effects of urolithin A, a gut microbial metabolite of ellagic acid, our aim was to explore the potential use of urolithin A in the prevention of cisplatin-induced nephrotoxicity in an experimental rat model. For this purpose, animals received a single intraperitoneal dose of cisplatin (5 mg/kg body weight). Six hours prior to cisplatin administration, rats were orally treated with either ellagic acid or urolithin A (50 mg/kg body weight), followed by a daily dose of these compounds during the next 5 days. At the end, plasma and kidneys were collected for analysis. Cisplatin-induced kidney damage was revealed by a significant rise in the plasma creatinine levels accompanied by significant morphologic changes in tubules, T cell Ig and mucin domain-containing protein-1, ionized calcium-binding adapter molecule 1, as well as a marked increase in the number of apoptotic cells localized in tubules. Cisplatin also reduced nitric oxide synthase 3 and nuclear factor kappa-light-chain-enhancer of activated B cells resulting in regulation of various inflammatory cytokines. Urolithin A effectively attenuated cisplatin-induced kidney damage and showed significantly greater effect than its precursor ellagic acid on preserving the normal kidney architecture by downregulating the proinflammatory cytokines. In summary, urolithin A mitigates cisplatin-induced nephrotoxicity in rats by modulation of the inflammatory cascade and inhibition of the proapoptotic pathway.

Topics: Animals; Apoptosis; Biomarkers; Body Weight; Cisplatin; Coumarins; Disease Models, Animal; Inflammation; Kidney; Male; Organ Size; Rats; Rats, Sprague-Dawley

Urolithin A is a major metabolite produced by rats and humans after consumption of pomegranate juice or pure ellagitannin geraniin. In this study, we investigated the anti-inflammatory effect of urolithin A on carrageenan-induced paw edema in mice. The volume of paw edema was reduced at 1h after oral administration of urolithin A. In addition, plasma in treated mice exhibited significant oxygen radical antioxidant capacity (ORAC) scores with high plasma levels of the unconjugated form at 1h after oral administration of urolithin A. These results indicate strong associations among plasma urolithin A levels, the plasma ORAC scores, and anti-inflammatory effects and may help explain a mechanism by which ellagitannins confer protection against inflammatory diseases.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Coumarins; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Discovery; Drug Evaluation, Preclinical; Edema; Free Radical Scavengers; Glucosides; Glucuronides; Humans; Hydrolyzable Tannins; Lythraceae; Mice; Mice, Inbred ICR; Rats

Whether the beneficial effects of pomegranate are due to the ellagitannins or to their microbiota-derived urolithins is not known. Our objectives were to evaluate the effects of pomegranate intake and its main microbiota-derived metabolite urolithin-A (UROA) on colon inflammation and to assess whether UROA is the main anti-inflammatory compound. In addition, the effect of the inflammation on the phenolic metabolism was also explored. Male Fisher rats were fed with 250 mg kg(-1) day(-1) pomegranate extract (PE) or 15 mg kg(-1) day(-1) UROA for 25 days. Dextran sodium sulfate (5%) (DSS) was administered for the five last days and then rats were euthanized. DSS is a well-known model of inflammatory bowel disease. Colon tissue damage, microbiota changes, antioxidant status, prostaglandin E(2) (PGE(2)), nitric oxide production, inducible nitric oxide synthase (iNOS), prostaglandin E synthase (PTGES), gene expression (microarrays and RT-PCR) and polyphenol metabolism (LC-MS-MS) were evaluated. Both PE and UROA decreased inflammation markers (iNOS, cycloxygenase-2, PTGES and PGE(2) in colonic mucosa) and modulated favorably the gut microbiota. The G(1) to S cell cycle pathway was up-regulated in both groups. UROA group showed various down-regulated pathways, including that of the inflammatory response. PE, but not UROA, decreased oxidative stress in plasma and colon mucosa. Only UROA preserved colonic architecture. The normal formation of urolithins in PE-fed rats was prevented during inflammation. Our results suggest that UROA could be the most active anti-inflammatory compound derived from pomegranate ingestion in healthy subjects, whereas in colon inflammation, the effects could be due to the nonmetabolized ellagitannin-related fraction.

Topics: Animals; Base Sequence; Chromatography, Liquid; Colitis; Colon; Coumarins; Disease Models, Animal; DNA Primers; Gene Expression Regulation; Lythraceae; Male; Phenols; Plant Extracts; Rats; Rats, Inbred F344; Reverse Transcriptase Polymerase Chain Reaction; Tandem Mass Spectrometry