Urolithin A

Urolithin A is a metabolite generated from ellagic acid and ellagitannins, acting as a potent inhibitor of tyrosinase(IC₅₀ value of 71.44±10.07µmol/L) and Monoamine Oxidase A(IC₅₀ value of 29.41±9.01µmol/L)^[1]. Urolithin A can enhance mitophagy and mitochondrial function, and reduce excessive inflammatory response, which is used in anti-cancer and anti-inflammatory research^[2].

In vitro, Urolithin A can inhibit the cell growth of HCT116 colon cancer cells by >50% with an IC₅₀ value of 39.2µmol/L after 48h and 19.6µmol/L after 72h^[3]. Urolithin A (30μmol/L, 24h) significantly inhibited new adipocyte formation and attenuated triglyceride accumulation by reducing triglyceride (TG) accumulation and lipogenic protein and gene expression, while increasing fatty acid (FA) oxidation in adipocytes and Huh7 hepatoma cells^[4]. Pretreatment with Urolithin A (40µmol/L) for 2 hours inhibited lipopolysaccharide-induced activation of PI3-K/Akt and MAPK signal pathways in RAW 264 macrophages^[5].

In vivo, Urolithin A treatment (20mg/kg/day, p.o.) for 42 days inhibited tumor growth, reduced AKT and p70S6K phosphorylation, decreased proliferation, and increased apoptosis in both PANC1 and MiaPaCa2 xenograft mouse models^[6]. Oral administration of Urolithin A (20mg/kg/day) for 8 weeks significantly ameliorated the development of osteoarthritis and reduced the degree of cartilage surface calcification in the mouse model of destabilization of the medial meniscus (DMM)^[7]. Intraperitoneal injection of Urolithin A (2.5mg/kg/day) for 7 consecutive days successfully upregulated Nrf2 expression and ameliorated myocardial injury and fibrosis in a rat model of myocardial infarction^[8].

References:
[1] Cásedas G, Les F, Choya-Foces C, et al. The metabolite urolithin-A ameliorates oxidative stress in neuro-2a cells, becoming a potential neuroprotective agent[J]. Antioxidants, 2020, 9(2): 177.
[2] D’Amico D, Andreux P A, Valdés P, et al. Impact of the natural compound urolithin A on health, disease, and aging[J]. Trends in molecular medicine, 2021, 27(7): 687-699.
[3] Norden E, Heiss E H. Urolithin A gains in antiproliferative capacity by reducing the glycolytic potential via the p53/TIGAR axis in colon cancer cells[J]. Carcinogenesis, 2019, 40(1): 93-101.
[4] Kang I, Kim Y E, Tomás‐Barberán F A, et al. Urolithin A, C, and D, but not iso‐urolithin A and urolithin B, attenuate triglyceride accumulation in human cultures of adipocytes and hepatocytes[J]. Molecular nutrition & food research, 2016, 60(5): 1129-1138.
[5] Komatsu W, Kishi H, Yagasaki K, et al. Urolithin A attenuates pro-inflammatory mediator production by suppressing PI3-K/Akt/NF-κB and JNK/AP-1 signaling pathways in lipopolysaccharide-stimulated RAW264 macrophages: Possible involvement of NADPH oxidase-derived reactive oxygen species[J]. European journal of pharmacology, 2018, 833: 411-424.
[6] Totiger T M, Srinivasan S, Jala V R, et al. Urolithin A, a novel natural compound to target PI3K/AKT/mTOR pathway in pancreatic cancer[J]. Molecular cancer therapeutics, 2019, 18(2): 301-311.
[7] Fu X, Gong L F, Wu Y F, et al. Urolithin A targets the PI3K/Akt/NF-κB pathways and prevents IL-1β-induced inflammatory response in human osteoarthritis: in vitro and in vivo studies[J]. Food & Function, 2019, 10(9): 6135-6146.
[8] Chen P, Pei J, Wang X, et al. Gut bacterial metabolite Urolithin A inhibits myocardial fibrosis through activation of Nrf2 pathway in vitro and in vivo[J]. Molecular Medicine, 2022, 28(1): 19.