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, Wataru; Kishi, Hisashi; Yagasaki, Kazumi; Ohhira, Shuji

doi:10.1016/j.ejphar.2018.06.023

Cited by 76 publications

(49 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One unequivocal response we routinely observed upon UroA administration was the remarkable suppression of inflammation . In particular, we saw a significant reduction in the expression of proinflammatory markers, cytokines, and chemokines in liver, adipose, and macrophages of UroA‐injected mice (Figures , , and ).…”

Section: Discussionmentioning

confidence: 75%

Urolithin A, a Gut Metabolite, Improves Insulin Sensitivity Through Augmentation of Mitochondrial Function and Biogenesis

Toney

Fan

Xian

et al. 2019

Obesity

View full text Add to dashboard Cite

Objective Urolithin A (UroA) is a major metabolite of ellagic acid produced following microbial catabolism in the gut. Emerging evidence has suggested that UroA modulates energy metabolism in various cells. However, UroA’s physiological functions related to obesity and insulin resistance remain unclear. Methods Male mice were intraperitoneally administrated either UroA or dimethyl sulfoxide (vehicle) along with a high‐fat diet for 12 weeks. Insulin sensitivity was evaluated via glucose and insulin tolerance tests and acute insulin signaling. The effects of UroA on hepatic triglyceride accumulation, adipocyte size, mitochondrial DNA content, and proinflammatory gene expressions were determined. The impact of UroA on macrophage polarization and mitochondrial respiration were assessed in bone marrow–derived macrophages. Results Administration of UroA (1) improved systemic insulin sensitivity, (2) attenuated triglyceride accumulation and elevated mitochondrial biogenesis in the liver, (3) reduced adipocyte hypertrophy and macrophage infiltration into the adipose tissue, and (4) altered M1/M2 polarization in peritoneal macrophages. In addition, UroA favored macrophage M2 polarization and mitochondrial respiration in bone marrow‐derived macrophages. Conclusions UroA plays a direct role in improving systemic insulin sensitivity independent of its parental compounds. This work supports UroA’s role in the metabolic benefits of ellagic acid–rich foods and highlights the significance of its microbial transformation in the gut.

show abstract

Section: Discussionmentioning

confidence: 75%

Urolithin A, a Gut Metabolite, Improves Insulin Sensitivity Through Augmentation of Mitochondrial Function and Biogenesis

Toney

Fan

Xian

et al. 2019

Obesity

View full text Add to dashboard Cite

show abstract

“…Once stimulated by IL-1β, NF-κB p65 translocates into the nucleus where it stimulates the expression of inflammatory mediators such as iNOS, COX-2, and MMPs, among these factors, iNOS catalyzes NO, which stimulates the secretion of MMPs and represses collagen II and proteoglycan synthesis to cause ECM degradation [21,39]. Previous studies demonstrated that UA could attenuate lipopolysaccharide-induced inflammation by inhibiting activation of the MAPK and NF-κB pathways and alleviate oxidized low-density lipoprotein-induced endothelial dysfunction by modulating MAPK signaling [42,43]. Our results demonstrated that IL-1β activated ERK, JNK, and p38; upregulated levels of phosphorylated p65; and increased nuclear translocation of p65.…”

Section: Discussionmentioning

confidence: 99%

Urolithin a attenuates IL-1β-induced inflammatory responses and cartilage degradation via inhibiting the MAPK/NF-κB signaling pathways in rat articular chondrocytes

et al. 2020

View full text Add to dashboard Cite

Background: Osteoarthritis (OA) is characterized by inflammation and extracellular matrix (ECM) degradation and is one of the most common chronic degenerative joint diseases that causes pain and disability in adults. Urolithin A (UA) has been widely reported for its anti-inflammatory properties in several chronic diseases. However, the effects of UA on OA remain unclear. The aim of the current study was to investigate the anti-inflammatory effects and mechanism of UA in interleukin-1β (IL-1β)-induced chondrocytes. Results: No marked UA cytotoxicity was noted, and UA protected cartilage from damage following IL-1β stimulation in micromasses. Moreover, UA promoted the expression of anabolic factors including Sox-9, Collagen II, and Aggrecan while inhibiting the expression of catabolic factors such as matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS-4) in rat chondrocytes. Protective effects of UA were also observed in ex vivo organ culture of articular cartilage. Mechanistically, IL-1β significantly activated and upregulated the expression of pERK 1/2, p-JNK, p-P38, and p-P65, while UA protected chondrocytes against IL-1β-induced injury by activating the mitogen-activated kinase (MAPK)/nuclear factor-κB (NF-κB) signaling pathways. Conclusion: Our results provide the evidence that UA could attenuate IL-1β-induced cell injury in chondrocytes via its anti-inflammatory action. UA may be a promising therapeutic agent in the treatment of OA.

show abstract

“…González-Sarrías et al [51] reported that ≥ 10 μM EA and UA mitigated the inflammatory state in human colonic fibroblasts that induced inflammation by IL-1β via inhibiting the activation of NF-kB and the p38 MAPK pathway. In addition, Komatu et al [16] reported that pretreatment with 40 μM UA inhibited the phosphorylation of p38 and JNK in inflammation-induced RAW264 macrophages induced by lipopolysaccharide, and also the formation of various proinflammatory mediators such as TNF-a, IL-6, and NO. In addition, p38 MAPK inhibitors are potential drug treatments for AD, and play an important role in the production of Aβ42-induced proinflammatory cytokines [52].…”

Section: Discussionmentioning

confidence: 99%

“…Ellagitannins (ETs) are hydrolyzed into ellagic acid (EA) in the body after ingestion of polyphenols in pomegranates, walnuts, and berries. ETs and EA have excellent antioxidant and cell-protective abilities but they are also limited in having low bioavailabilities; thus, studies have increasingly investigated gut microbial-derived metabolites such as urolithins (uros) [15,16]. Uros have been found in various forms such as Uro-M5, Uro-M6, Uro-M7, Uro-D, Uro-C, Uro-B, Uro-A, and isoUro-A.…”

Section: Introduction 1)mentioning

confidence: 99%

Neuroprotective effects of urolithin A on H₂O₂-induced oxidative stress-mediated apoptosis in SK-N-MC cells

2020

View full text Add to dashboard Cite

BACKGROUND/OBJECTIVES: Oxidative stress causes cell damage and death, which contribute to the pathogenesis of neurodegenerative diseases. Urolithin A (UA), a gut microbial-derived metabolite of ellagitannins and ellagic acid, has high bioavailability and various health benefits such as antioxidant and anti-inflammatory effects. However, it is unknown whether it has protective effects against oxidative stress-induced cell death. We investigated whether UA ameliorates H2O2-induced neuronal cell death. MATERIALS/METHODS: We induced oxidative damage with 300 μM H2O2 after UA pretreatment at concentrations of 1.25, 2.5, and 5 μM in SK-N-MC cells. Cytotoxicity and cell viability were determined using the CCK-8 assay. The formation of reactive oxygen species (ROS) was measured using a 2,7-dichlorofluorescein diacetate assay. Hoechst 33342 staining was used to characterize morphological changes in apoptotic cells. The expressions of apoptosis proteins were measured using Western blotting. RESULTS: UA significantly increased cell viability and decreased intracellular ROS production in a dose-dependent manner in SK-N-MC cells. It also decreased the Bax/Bcl-2 ratio and the expressions of cytochrome c, cleaved caspase-9, cleaved caspase-3, and cleaved PARP. In addition, it suppressed the phosphorylation of the p38 mitogen-activated protein kinase (MAPK) pathway. CONCLUSIONS: UA attenuates oxidative stress-induced apoptosis via inhibiting the mitochondrial-related apoptosis pathway and modulating the p38 MAPK pathway, suggesting that it may be an effective neuroprotective agent.

show abstract

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

Cited by 76 publications

References 54 publications

Urolithin A, a Gut Metabolite, Improves Insulin Sensitivity Through Augmentation of Mitochondrial Function and Biogenesis

Urolithin A, a Gut Metabolite, Improves Insulin Sensitivity Through Augmentation of Mitochondrial Function and Biogenesis

Urolithin a attenuates IL-1β-induced inflammatory responses and cartilage degradation via inhibiting the MAPK/NF-κB signaling pathways in rat articular chondrocytes

Neuroprotective effects of urolithin A on H₂O₂-induced oxidative stress-mediated apoptosis in SK-N-MC cells

Contact Info

Product

Resources

About

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

Cited by 76 publications

References 54 publications

Urolithin A, a Gut Metabolite, Improves Insulin Sensitivity Through Augmentation of Mitochondrial Function and Biogenesis

Urolithin A, a Gut Metabolite, Improves Insulin Sensitivity Through Augmentation of Mitochondrial Function and Biogenesis

Urolithin a attenuates IL-1β-induced inflammatory responses and cartilage degradation via inhibiting the MAPK/NF-κB signaling pathways in rat articular chondrocytes

Neuroprotective effects of urolithin A on H2O2-induced oxidative stress-mediated apoptosis in SK-N-MC cells

Contact Info

Product

Resources

About

Neuroprotective effects of urolithin A on H₂O₂-induced oxidative stress-mediated apoptosis in SK-N-MC cells