Urolithin A

• CAT Number: R022477
• CAS Number: 1143-70-0
• Molecular Formula: C13H8O4
• Molecular Weight: 228.20
• Purity: ≥95%
• Synonyms: 3,8-Hydroxydibenzo-α-pyrone; 3,8-Dihydroxyurolithin; 2’,7-Dihydroxy-3,4-benzocoumarin; δ-Lactone 2’,4,4’-Trihydroxy-2-biphenylcarboxylic Acid
• Target: NF-κB
• Storage: -20°C
• IUPAC Name: 3,8-dihydroxybenzo[c]chromen-6-one
• InChI: InChI=1S/C13H8O4/c14-7-1-3-9-10-4-2-8(15)6-12(10)17-13(16)11(9)5-7/h1-6,14-15H
• InChIKey: RIUPLDUFZCXCHM-UHFFFAOYSA-N
• SMILES: C1=CC2=C(C=C1O)C(=O)OC3=C2C=CC(=C3)O

Urolithin A（Cat No.:R022477）is a natural metabolite derived from ellagitannins found in fruits like pomegranates and berries. Known for its mitophagy-enhancing properties, Urolithin A promotes the selective recycling of damaged mitochondria, supporting cellular health and longevity. It has gained attention for potential benefits in aging, muscle function, and neuroprotection by improving mitochondrial function and reducing oxidative stress. Urolithin A is widely studied for its anti-inflammatory and antioxidant effects, making it a promising compound in research focused on aging-related conditions, metabolic health, and neurodegenerative diseases.

Reference

1. Mol Cancer Ther. 2019 Feb;18(2):301-311. doi: 10.1158/1535-7163.MCT-18-0464. Epub 2018 Nov 7.Urolithin A, a Novel Natural Compound to Target PI3K/AKT/mTOR Pathway in Pancreatic Cancer.Totiger TM(#)(1), Srinivasan S(#)(1), Jala VR(2), Lamichhane P(1), Dosch AR(1), Gaidarski AA 3rd(1), Joshi C(1), Rangappa S(3), Castellanos J(4), Vemula PK(5), Chen X(6), Kwon D(6), Kashikar N(7), VanSaun M(1), Merchant NB(1), Nagathihalli NS(8).

 

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy and is highly resistant to standard treatment regimens. Targeted therapies against KRAS, a mutation present in an overwhelming majority of PDAC cases, have been largely ineffective. However, inhibition of downstream components in the KRAS signaling cascade provides promising therapeutic targets in the management of PDAC and warrants further exploration. Here, we investigated Urolithin A (Uro A), a novel natural compound derived from pomegranates, which targets numerous kinases downstream of KRAS, in particular the PI3K/AKT/mTOR signaling pathways. We showed that treatment of PDAC cells with Uro A blocked the phosphorylation of AKT and p70S6K in vitro, successfully inhibited the growth of tumor xenografts, and increased overall survival of Ptf1aCre/+;LSL-KrasG12D/+;Tgfbr2flox/flox (PKT) mice compared with vehicle or gemcitabine therapy alone. Histologic evaluation of these Uro A-treated tumor samples confirmed mechanistic actions of Uro A via decreased phosphorylation of AKT and p70S6K, reduced proliferation, and increased cellular apoptosis in both xenograft and PKT mouse models. In addition, Uro A treatment reprogrammed the tumor microenvironment, as evidenced by reduced levels of infiltrating immunosuppressive cell populations such as myeloid-derived suppressor cells, tumor-associated macrophages, and regulatory T cells. Overall, this work provides convincing preclinical evidence for the utility of Uro A as a therapeutic agent in PDAC through suppression of the PI3K/AKT/mTOR pathway.

 

2. Eur J Pharmacol. 2018 Aug 15;833:411-424. doi: 10.1016/j.ejphar.2018.06.023. Epub 2018 Jun 20.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.Komatsu W(1), Kishi H(2), Yagasaki K(3), Ohhira S(2).

 

Urolithin A, a gut microbial metabolite of ellagic acid, is reported to exert anti-inflammatory effects in vitro and in vivo. However, complete mechanisms underlying the regulation of inflammatory responses by urolithin A remain unclear. This study aimed to evaluate the anti-inflammatory potential of urolithin A and its underlying mechanisms in lipopolysaccharide (LPS)-stimulated RAW264 macrophages. Urolithin A significantly attenuated the pro-inflammatory mediator production in LPS-stimulated RAW264 and mouse peritoneal macrophages. This compound significantly suppressed the LPS-elicited nuclear factor-κB(NF-κB) and activator protein-1 (AP-1) activation. The phosphorylation of Akt and c-Jun N-terminal kinase (JNK) was also inhibited by the treatment with urolithin A. Through experiments using kinase inhibitors, urolithin A abolished the LPS-induced phosphatidylinositol 3-kinase (PI3-K)/Akt/NF-κB and JNK/AP-1 signaling pathways, resulting in suppression of pro-inflammatory mediator production. Furthermore, treatment with this compound significantly reduced the intracellular accumulation of reactive oxygen species, which are known to act as secondary messengers in the activation of redox-sensitive transcription factors NF-κB and AP-1. Urolithin A treatment also diminished the LPS-evoked activation of NADPH oxidase (NOX), which is the main source of reactive oxygen species in activated macrophages. The inhibition of this activity by urolithin A led to the prevention of LPS-elicited NF-κB and AP-1 activation as well as Akt and JNK phosphorylation, resulting in the reduction of pro-inflammatory mediator production. Collectively, these results indicate that urolithin A treatment attenuates pro-inflammatory mediator production by suppressing NOX-derived reactive oxygen species-mediated PI3-K/Akt/NF-κB and JNK/AP-1 signaling pathways in LPS-stimulated macrophages.

 

3. Food Funct. 2019 Sep 1;10(9):6135-6146. doi: 10.1039/c9fo01332f. Epub 2019 Sep 9.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.Fu X(1), Gong LF(2), Wu YF(1), Lin Z(1), Jiang BJ(1), Wu L(1), Yu KH(1).

 

Osteoarthritis (OA) is a degenerative joint disease, whose progression is closely related to the inflammatory environment. Urolithin A (UA), a natural metabolite of a class of compounds (ellagitannins and ellagic acid) found in pomegranates and other fruits and nuts, has been proved to exert anti-inflammatory effects in a variety of diseases. However, the exact role of UA in OA development is still unclear. In the present study, we examined the latent mechanism of UA and its protective role in the progression of OA by both in vitro and in vivo experiments. In vitro, UA inhibited the interleukin-1 beta 

(IL-1β) induced over-production of nitric oxide (NO), prostaglandin E2 (PGE2), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in a concentration-dependent 

manner in human OA chondrocytes. Furthermore, by downregulating the expression of metalloproteinase 13 (MMP13) and thrombospondin motifs 5 (ADAMTS5), UA attenuated the degradation of the extracellular matrix (ECM) induced by IL-1β. 

Mechanistically, UA was found to suppress the activation of PI3K/Akt/NF-κB pathways. In vivo, in a surgically induced mouse OA model, UA-induced protective effects in OA development could be detected. In summary, this research suggested that UA may be adopted as a new therapeutic agent for the treatment of OA.