In recent years, CeO nanoparticles are promising biomaterials due to their excellent biocompatibility and antioxidant properties. This study utilizes a methacrylated gelatin (GelMA) hydrogel platform to construct a dual-functional composite material, CeUA@GelMA, by co-loading CeO nanoparticles with urolithin A (UA). This material possesses both reactive oxygen species (ROS) scavenging and mitophagy activation capabilities, aiming to overcome the bottleneck in cartilage regeneration by regulating mitochondrial homeostasis. experiments confirmed that this material significantly reduces ROS levels within BMSCs under oxidative stress, maintains mitochondrial membrane potential, and promotes chondrogenic differentiation by upregulating genes such as Sox9, Col II, and ACAN. studies demonstrated that the CeUA@GelMA group achieved hyaline-like cartilage regeneration 8 weeks post-operation. The surface roughness of the newly formed cartilage was comparable to that of natural cartilage, with collagen and glycosaminoglycan density approaching normal cartilage levels. In summary, this research offers an innovative strategy and hydrogel material for cartilage tissue engineering through the regulation of mitochondrial homeostasis.
Ma C, Hua B, Wang H, Ma T, Lv Q, Yan Z, Materials today. Bio
Sleep loss drives metabolic and immune dysfunction, yet the epigenetic links to inflammation remain poorly defined. Using larval zebrafish with a continuous-swim paradigm, we demonstrate that acute sleep deprivation (SD) induces sleep fragmentation, systemic oxidative stress, and sustained neutrophilic inflammation─phenotypes associated with elevated histone H3K18 lactylation (H3K18la), an epigenetic modification from glycolytic lactate. Critically, gut microbiota metabolite Urolithin A (UA) exerts potent protection: it downregulates ROS-generating and glycolysis-related genes and reduces intracellular lactate and histone lactylation, collectively disrupting the pathogenic ROS-H3K18la feedback loop. Mechanistically, UA reduces aberrant H3K18la deposition at the and promoters to suppress transcription. Functional assays confirm that UA rescues SD-impaired inflammation resolution, reduces excessive neutrophil recruitment/retention at injury sites, and restores antioxidant homeostasis. These findings identify UA as a multitarget modulator that mitigates SD-associated inflammation via the ROS-H3K18la-inflammation axis, highlighting its translational potential for sleep loss-related immune/metabolic disorders.
Zhou R, Li K, Zhang H, Wang Y, Wei C, Fan S, Yin Z, Zhang X, Ren D, Journal of agricultural and food chemistry
The decline in productivity and increased immune stress associated with hepatic oxidative stress in aging laying hens limit the efficiency of egg production. Urolithin A (UA), a natural metabolite, has been shown to activate the Nrf2 antioxidant pathway in mammals; however, its effects and underlying mechanisms in laying hens remain unclear. This study aimed to systematically evaluate the dose-response effects of dietary UA on the health and production performance of laying hens, with an emphasis on its role in activating the Nrf2 pathway. Fifty (45-week-old) Roman Pink laying hens were randomly assigned to one of five dietary treatments: a basal diet supplemented with 0, 50, 200, 400, or 800 mg/kg UA for 6 weeks. The production performance, organ indices, serum and liver lipid profiles, antioxidant status, immune markers, liver histology, and Nrf2 pathway-related mRNA and protein expression were assessed. An in vitro model of primary chicken hepatocytes was also used to validate the direct effects of UA. Compared with the control group (0 mg/kg UA), 200 mg/kg UA supplementation showed significantly improved the laying rate and egg weight, reduced the feed-to-egg ratio, and lowered the serum total cholesterol and triglyceride levels (P < 0.05). This optimal dose also enhanced the total antioxidant capacity and superoxide dismutase and glutathione peroxidase activities in both the serum and liver, decreased the malondialdehyde levels, and increased the immunoglobulin (IgY and IgA) concentrations (P < 0.05). UA at 400 and 800 mg/kg doses did not enhance egg laying (P > 0.05), but significantly reduced liver and abdominal fat indices (P < 0.05). All UA doses lowered hepatic TC content (P < 0.05), but only the higher doses (400 and 800 mg/kg) significantly decreased liver VLDL-C levels (P < 0.05). At the molecular level, 200 mg/kg UA significantly upregulated the mRNA and protein expression of Nrf2 and its key downstream targets in the liver (P < 0.05). These effects were corroborated in vitro, where 5 μmol/L UA significantly promoted hepatocyte viability and upregulated Nrf2 and downstream mRNA expression (P < 0.05). This study is the first to provide systematic evidence that supplementing with 200 mg/kg UA may enhance late-phase laying performance by boosting antioxidant capacity, regulating lipid metabolism, and improving immune function, likely through activation of the hepatic Nrf2 pathway, suggesting its potential as a natural feed additive for sustained peak production.
Wu L, Zhang Y, Peng L, Ye L, Zhao X, Poultry science
Over the past decade, research on urolithins has expanded significantly due to their role as mediators between polyphenol-rich diets and human health. Understanding the relationships between ellagitannin intake, gut microbiota composition, and urolithin production is essential for evaluating their biological effects and nutraceutical potential. The primary objective of this review is to critically summarise current knowledge on urolithins, bioactive metabolites derived from ellagitannins in plant-based foods, with a focus on their biosynthesis, bioavailability, protein interactions, and potential therapeutic applications. A comprehensive literature search was conducted using PubMed, Scopus, and Google Scholar to identify studies on urolithin biosynthesis, absorption, transport mechanisms, protein binding, and incorporation into extracellular vesicles. Relevant articles were critically analysed to synthesise current evidence and highlight emerging concepts. Key findings indicate that after absorption, urolithins bind to serum albumin, which facilitates their transport to target tissues, exerting anti-inflammatory and antioxidant actions. Recent evidence also shows that urolithins can be packaged into extracellular vesicles, suggesting novel mechanisms for intracellular transport and potential therapeutic applications. This review highlights gaps in current knowledge and proposes directions for future research to optimise their therapeutic potential.
Zelenović N, Kojadinović M, Popović M, Molecules (Basel, Switzerland)
INTRODUCTION: Sarcopenia, characterized by the progressive loss of muscle mass and function, may be alleviated by ellagic acid (EA) through its microbial metabolite urolithin A (Uro-A). However, the low in vivo conversion efficiency of EA to Uro-A limits its clinical utility.
OBJECTIVES: This study aimed to develop a gut microbiota-targeted dietary strategy to enhance Uro-A biosynthesis and improve muscle performance.
METHODS: A combinatorial approach using EA and fructooligosaccharides (FOS) was applied in vivo to modulate microbial metabolism. Gut microbiota composition, urolithin profiles, and muscle performance were assessed. Mechanistic roles of key bacterial species were further explored.
RESULTS: EA and FOS synergistically improved muscle endurance and strength by enhancing Uro-A production, compared with either intervention alone. Mechanistically, we identified a previously unrecognized two-step cooperative pathway: Bifidobacterium pseudolongum initiated EA metabolism by converting it to urolithin C (Uro-C), and while Enterococcus faecalis, identified here for the first time, catalyzed the conversion of Uro-C to Uro-A. This newly uncovered cross-feeding partnership between the two species proved essential for maximizing Uro-A biosynthesis and mediating the physiological benefits.
CONCLUSION: This study demonstrates a proof-of-concept strategy to boost gut microbial Uro-A biosynthesis through dietary modulation, providing a novel and cost-effective approach for sarcopenia prevention and management.
Zhang L, Jiang Z, Liu D, Yu C, Wang Y, Zhang H, Wu J, Pan H, Ye X, Chen S, Journal of advanced research
BACKGROUND: Urolithin B (UB) is a gut microbial metabolite derived from dietary ellagitannins found in foods such as pomegranates, berries, and nuts. Although UB has demonstrated antitumor potential, possibly through gut microbiota modulation, its specific role and underlying mechanisms in lung cancer remain unclear.
OBJECTIVES: This study aimed to investigate the antitumor effects of UB on lung cancer suppression and to explore the potential involvement of autophagy and gut microbiota in these effects.
METHODS: We employed in vitro and in vivo approaches. Lung cancer cells were treated with UB at varying concentrations to assess proliferation and autophagy. Transcriptomic analysis was conducted to identify key regulatory pathways. A tumor-bearing mouse model was used to evaluate the effects of oral UB administration, and gut microbiota changes were analyzed via 16S rRNA sequencing.
RESULTS: UB inhibited lung cancer cell growth in a dose- and time-dependent manner, primarily by inducing autophagy rather than apoptosis, as evidenced by increased microtubule-associated protein 1A/1B-light chain 3-II concentrations. Transcriptomic profiling and protein analysis revealed that UB treatment was associated with a change in the status of the AMP-activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) pathway, a key regulator of autophagy. In vivo, oral UB administration significantly suppressed tumor growth, enhanced autophagic activity, and modulated the expression of autophagy-related proteins. Furthermore, 16S rRNA sequencing revealed that UB induced an enrichment of beneficial gut bacteria, including Lactobacillus and Desulfovibrio.
CONCLUSIONS: These findings highlight UB as a promising dietary-derived metabolite for lung cancer prevention and therapy. Our study suggests that UB exerts its antitumor effects in part through the induction of autophagy associated with the AMPK/mTOR pathway and concomitant modulation of the gut microbiota, emphasizing the critical role of food-gut interactions in cancer management.
Sun J, Li X, Sun L, Chen B, Duan J, The Journal of nutrition
Urolithin A (UA) is a metabolite of natural polyphenols tannic acid and tannic acid produced by the gut microbiota that has multiple pharmacological effects. However, the effects of UA on osteoarthritis (OA) have not been reported. The aim of this study was to study the effect of UA on OA and clarify the possible mechanism. The mouse OA model was established and the mouse chondrocytes were isolated and cultured. The effect of UA on the cell viability of chondrocytes was tested by MTT assay. The levels of prostaglandin E2 (PGE2), Nitric Oxide (NO), Matrix Metalloproteinase-1 (MMP1), and Matrix Metalloproteinase-3 (MMP3) were measured by the detection kits. The expression of ferroptosis, nuclear factor-kappa B (NF-κB), and Adenosine Monophosphate-Activated Protein Kinase (AMPK) pathway related proteins were detected by western blot. The results showed that UA could attenuate the cartilage tissue injury, MMP1, and MMP3 expression in vivo. UA significantly suppressed PGE2, NO, MMP1, and MMP3 production, and NF-κB activation induced by Interleukin-1 beta (IL-1β). UA attenuated IL-1β-induced MDA, Fe, and up-regulated glutathione (GSH) production, GPX4, and ferritin expression, which suggested UA could attenuate IL-1β-induced ferroptosis. Furthermore, UA could upregulate the expression of AMPK, and downregulate the expression of mTOR and HIF-1αinduced by IL-1β. In addition, AMPK inhibitor compound C prevented the inhibition of UA on IL-1β-induced PGE2, NO, MMP1, MMP3, and ferroptosis. In conclusion, the data indicated that UA exhibited therapeutic effects against OA through inhibiting inflammation and ferroptosis via the AMPK/mTOR/HIF-1αsignaling pathway.
Urolithin A is an anti-aging and anti-inflammatory gut bacterial metabolite derived from ellagic acid (EA), a polyphenol abundant in berries and nuts. The conversion of EA to urolithin A involves multiple chemically challenging phenol dehydroxylation steps that produce urolithins with varying bioactivities. Despite their biological and chemical significance, the bacterial enzymes responsible for urolithin production remain largely unidentified. Here, we use differential gene expression analysis, anaerobic protein production, and enzyme assays to identify members of two distinct molybdenum enzyme families (the DMSO reductase family and the xanthine oxidase family) capable of regioselective dehydroxylation and urolithin generation. These two enzyme families have distinct substrate requirements, suggesting they employ different catalytic mechanisms for phenol dehydroxylation. Multiomics analysis of a human cohort uncovers decreased levels of urolithin A and genes encoding urolithin A-producing enzymes in patients with inflammatory bowel disease (IBD), implying reduced health effects of EA consumption in this setting. Together, this study elucidates the molecular basis of urolithin production, expands the known enzymatic repertoire of the human gut microbiome, and suggests a potential link between gut bacterial urolithin production and reduced host inflammation.
Bae M, Dong X, Avila-Pacheco J, Nguyen QD, Inyama F, Hill-Maini V, Clish CB, Balskus EP, Proceedings of the National Academy of Sciences of the United States of America
The increasing focus on longevity and cellular health has brought into the spotlight two key compounds, urolithin A (UroA) and spermidine, for their promising roles in autophagy and mitophagy. Urolithin A, a natural metabolite derived from ellagitannins, stimulates mitophagy through pathways such as PTEN induced kinase 1 (PINK1)/Parkin RBR E3 ubiquitin protein ligase (PRKN), leading to improved mitochondrial health and enhanced muscle function. However, spermidine, a polyamine found in various food sources, induces autophagy by regulating key signaling pathways such as 5′ AMP-activated protein kinase (AMPK) and sirtuin 1, thus mitigating age-related cellular decline and promoting cardiovascular and cognitive health. While both UroA and spermidine target cellular maintenance, they affect overlapping as well as distinct signalling pathways. Thus, they do not have completely identical effects, although they overlap in many ways, and offer varying benefits in terms of metabolic function, oxidative stress reduction and longevity. This review article aims to describe the mechanisms of action of UroA and spermidine not only on the maintenance of cellular health, which is mediated by the induction and maintenance of autophagy and mitophagy, but also on their potential clinical relevance. The analysis presented here suggests that although both compounds are safe and offer substantial health benefits and are involved in both autophagy and mitophagy, the role of UroA in mitophagy places it as a targeted intervention for mitochondrial health, whereas the broader influence of spermidine on autophagy and metabolic regulation may provide more comprehensive anti-ageing effects.
Borsky P, Holmannova D, Soukup O, Fiala Z, Maresova T, Hanzlova M, Philipp T, Borska L, Nutrition research reviews
Cisplatin remains a cornerstone of chemotherapy, but its clinical use is often limited by cisplatin-induced acute kidney injury, a condition driven by oxidative stress, inflammation, and mitochondrial dysfunction. Here, we developed naringenin-functionalized polyester nanoparticles (P2Ns-NAR) to enhance the oral delivery and therapeutic efficacy of urolithin A (UA), a mitochondrial-targeting metabolite with cytoprotective properties. The resulting formulation, P2Ns-NAR-UA, conferred kidney protection in vitro and in vivo, outperforming the nontargeted nanoparticle formulation (P2Ns-UA). Notably, in vivo efficacy was achieved at a 50% lower dose. Molecular docking studies suggest UA exhibits a favorable heme oxygenase-1 binding energy of -7.43 kcal/mol, supporting its potential as a promising drug candidate. Mechanistic studies demonstrated that P2Ns-NAR-UA upregulate heme oxygenase-1 and activate PTEN-induced putative kinase 1/Parkin-mediated mitophagy, promoting mitochondrial quality control and preserving dynamics by increasing mitofusin-1/2 and reducing dynamin-related protein 1 and mitochondrial fission protein 1 expression. Treatment also attenuated inflammatory cytokines (interleukin 6, interleukin 8, and tumor necrosis factor-α), immune activation markers (cluster of differentiation 80 and 45), and kidney injury biomarkers (neutrophil gelatinase-associated lipocalin, cystatin C, and osteopontin). Histological analysis confirmed reduced tubular damage and fibrosis. These findings establish P2Ns-NAR-UA as a promising oral therapeutic platform to mitigate cisplatin-induced acute kidney injury through coordinated modulation of inflammation, oxidative stress, and mitochondrial homeostasis. Further investigation in cisplatin-resistant cancer models is warranted to establish this platform's dual therapeutic potential and translational value. SIGNIFICANCE STATEMENT: This study shows that naringenin-functionalized polyester nanoparticles improves intestinal uptake of encapsulated agents through intestinal folate receptors. Naringenin-functionalized polyester nanoparticles loaded with urolithin A (P2Ns-NAR-UA) doubles the efficacy of polyester nanoparticles loaded with urolithin A, achieving comparable results at half the dose. The formulation enhances cell health, reduces inflammation, and restores kidney function, making it a promising adjuvant to cisplatin therapy by improving outcomes while minimizing toxicity.
Wahab AT, Ganugula R, Sheikh-Hamad D, Bolisetty S, Arora M, Kumar MNVR, The Journal of pharmacology and experimental therapeutics
BACKGROUND: Peripheral nerve injury (PNI) often results in incomplete recovery due to persistent neuroinflammation and mitochondrial dysfunction. Here, we investigated the therapeutic potential of Urolithin A (UA), a gut microbiota-derived metabolite, in promoting nerve regeneration by modulating mitophagy and inflammasome activation.
OBJECTIVE: To evaluate whether UA enhances peripheral nerve regeneration by activating TFEB-mediated mitophagy and inhibiting NLRP3 inflammasome activation.
METHODS: In a rat sciatic nerve crush injury model and Schwann cell cultures, UA effects were evaluated using behavioral tests, histological analysis, transmission electron microscopy, immunofluorescence, Western blotting, and molecular docking.
RESULTS: UA administration significantly improved sciatic functional index, reduced muscle atrophy, and enhanced axonal regeneration and remyelination. Mechanistically, UA promoted transcription factor EB (TFEB) nuclear translocation, upregulated autophagy-lysosomal genes, and facilitated clearance of damaged mitochondria, leading to reduced ROS levels and suppression of NLRP3 inflammasome activation. These effects were abolished by TFEB knockdown or autophagy inhibition, indicating a TFEB-dependent mechanism. Molecular docking suggested direct binding between UA and TFEB.
CONCLUSION: UA facilitates peripheral nerve repair by coupling TFEB-mediated mitophagy with NLRP3 inflammasome inhibition. This dual action provides a promising non-invasive therapeutic strategy for PNI and warrants further translational research.
Zhe Zhang, Shanying Xiao, Dongbu Tian, Tao Lin, Kongmei Luo, Dong Peng, Yixin Bo, Anhao Guo, Yujie Hu, Long Wu, Hede Yan, Int Immunopharmacol
We designed and synthesised 22 new urolithin derivatives (UDs) based on methyl-urolithin A (mUA) to identify anti-cancer drugs with high efficacy and low toxicity and evaluated their anti-cancer activities . Cytotoxicity tests were performed on three cell lines (DU145, T24, and HepG2) and a human normal cell line (HK-2). The half-inhibitory concentration (IC) of derivative UD-4c to hepatoma HepG2 cells (IC = 4.66 ± 0.12 μM) was significantly lower than that of sorafenib (IC =7.76 ± 0.12 μM), and exhibited less toxicity to HK-2 cells. Preliminary studies on the mechanism revealed that the derivative UD-4c could significantly inhibit the HepG2 cell growth and colony formation, block the HepG2 cell cycle in the G2/M phase, and induce apoptosis of HepG2 cells dose-dependently. The derivative UD-4c can be used as a potential lead compound to further develop new drugs for hepatocellular carcinoma treatment based on the evaluation of anti-cancer activity.
Tian M, Zhao L, Lan Y, Li C, Ling Y, Zhou B, Journal of enzyme inhibition and medicinal chemistry
Ocular inflammation is a major contributor to vision-threatening disorders, with phosphodiesterase 4 (PDE4), a key regulator of cAMP playing a central role in pro-inflammatory signaling. Although investigational PDE4 inhibitors like Rolipram (RP) show therapeutic promise, their systemic toxicity limits clinical application, underscoring the need for safer, targeted alternatives. Urolithin A (UA), a gut-derived metabolite of ellagic acid with emerging anti-inflammatory properties, was evaluated as a novel PDE4 inhibitor. Molecular docking revealed that UA binds with high affinity to the A-chain of PDE4A (-8.79 kcal/mol), forming unique π-π stacking and multiple hydrogen bonds. In contrast, RP binds preferentially to the B-chain with slightly lower affinity (-8.42 kcal/mol) and fewer stabilizing interactions. While both ligands engage similar catalytic residues, UA exhibited a more extensive binding profile, suggesting enhanced stability and specificity. In lipopolysaccharide (LPS)-stimulated human retinal pigment epithelial cells (ARPE-19), UA significantly inhibited PDE4A activity, elevated intracellular cAMP, and reduced key inflammatory mediators (NF-κB, IL-6, TNF-α), as demonstrated by immunofluorescence, ELISA, and gene expression analysis. These findings support UA's function as an anti-inflammatory agent by inhibiting PDE4A, highlighting its potential as a safer systemic or localized therapy for ocular inflammatory diseases.
Kondapaneni LP, Arora M, Scott EM, Kumar MNVR, Ganugula R, Pharmaceutical research
BACKGROUND: Amyloid β (Aβ) accumulation in the brains of patients with Alzheimer's disease (AD) contributes to cognitive impairment and neuronal damage. Urolithin A (UA), a gut microbiota-derived metabolite of ellagic acid, has been reported to cross the blood-brain barrier to exert anti-inflammatory and anti-oxidation effects in the brain. However, the molecular mechanisms of UA in AD were still unclear. This study aims to explore the neuroprotective effect and mechanism of UA on APP/PS1 mice and Aβ-injured N2a and PC12 cells.
METHODS: In this study, Morris water maze was used to detect the cognitive function. Immunofluorescence was used to detect the deposition of Aβ and the expression of voltage-dependent anion channel 1 (VDAC1) in the brains of APP/PS1 mice. Western blotting was used to detect the expression of VDAC1, AMPK pathway, PI3K pathway and autophagy-related proteins. CCK8 was used to detect the viability of Aβ-injured cells.
RESULTS: In this research, we found that UA improved cognitive dysfunction and reduced Aβ deposition in APP/PS1 mice. Furthermore, UA activated autophagy and upregulated the levels of autophagy-related proteins in both APP/PS1 mice and Aβ-injured N2a and PC12 cells. At the same time, UA down-regulated the phosphorylation level of PI3K/AKT/mTOR and up-regulated the phosphorylation level of AMPK in APP/PS1 mice and Aβ-injured N2a cells and PC12 cells. In addition, UA down-regulated VDAC1, consistent with the effect of VDAC1 antagonist DIDS (4'-diisothiocyano-2,2'-disulfonic acid stilbene). Importantly, the UA-induced activation of autophagy and modulation of the PI3K and AMPK pathways were reversed by VDAC1 overexpression.
CONCLUSION: These findings demonstrated that UA down-regulated VDAC1 played a key neuroprotective role on AD by inhibiting the PI3K/AKT/mTOR pathway and activating the AMPK pathway to promote autophagy.
Zhang B, Zhang X, Treebupachatsakul W, Pantan R, Kampan N, Phatsara M, Shi C, Narakornsak S, Acta histochemica
Recent studies have indicated that stress in the endoplasmic reticulum (ER) plays a role in the development of domoic acid-induced neurodegeneration. Urolithin A (Uro A) is an active metabolite of the plant polyphenol ellagic acid, which is generated by intestinal flora and offers positive health and biological benefits. Recent research has indicated that anthocyanins possess estrogenic properties and can boost the expression of estrogen receptor-α (ERα). In this study, we examined the effects of Uro A on cognitive deficits resulting from hippocampal mitochondrial dysfunction in mice exposed to domoic acid (DA) and explored the underlying mechanisms. Oral administration of Uro A to the DA-treated mice significantly improved their performance in behavioral tasks, such as step-through passive avoidance, Morris water maze, and open field test. These advancements were, to some extent, driven by the stimulation of mitochondrial biogenesis signaling through estrogen receptor-α and also by lowered expression levels of p47phox and gp91phox. A reduction in reactive oxygen species and protein carbonylation was noted, along with the inhibition of the signaling pathway related to ER stress. Moreover, Uro A greatly reduced ER stress-induced apoptosis, which prevented synaptic damage and restored the expression of memory-related proteins. The partial attenuation of the neuroprotective effects of Uro A in the mice given a combination of Uro A and DA, following the knockdown of ERα via short hairpin RNA, suggests that Uro A exerts its effects via several routes. Our findings imply that Uro A can be used to prevent and treat cognitive deficits associated with excitotoxicity and other brain disorders.
Chen P, Lei J, Li R, Liu R, Zhou B, Free radical biology & medicine
Urolithin A (UA), a gut microbiota-derived metabolite of ellagic acid, exhibits diverse biological activities. Emerging evidence suggests its anti-tumor potential, possibly mediated through gut microbiota modulation, yet its role in lung cancer remains unclear. In this study, UA dose- and time-dependently suppressed lung cancer cell proliferation. Mechanistically, UA triggered autophagy, as evidenced by increased LC3-II protein levels, and transcriptome analysis revealed this effect was mediated through inhibition of the PI3K/AKT/mTOR pathway. In vivo, UA supplementation markedly inhibited tumor growth in H1975 xenograft models, concomitant with enhanced autophagy and downregulation of associated proteins. Notably, 16S rRNA sequencing demonstrated that UA modulated gut microbiota composition, increasing Lactobacillus while decreasing Desulfovibrio abundance. Spearman's correlation analysis further linked these microbial shifts to altered expression of autophagy-related genes. Collectively, our findings highlight UA as a promising gut microbial metabolite for lung cancer intervention via coordinated autophagy induction and microbiota remodeling.
Zhang J, Li X, Sun L, Chen B, Zhang R, Duan J, The Journal of nutritional biochemistry
Mitochondria are key organelles that supply energy to the brain, and their dysfunction contributes to neurotoxicity induced by environmental toxins such as rotenone. Recently, oenological tannins (OTs) and their colonic metabolite, urolithin A (UA), have been emphasized due to their potential neuroprotective activity. However, their role in counteracting toxin-induced mitochondrial impairments remains unclear. Therefore, this study aimed to investigate the administration of OTs to rotenone (ROT)-induced mitochondrial dysfunction and oxidative stress, key contributors to neurotoxicity. We measured mitochondrial membrane potential (MMP), the activity of mitochondrial complex I (Grishchuk et al.), and aldehyde dehydrogenase 2 (ALDH2) to assess mitochondria and protein carbonyl (PC) levels. We also checked the presence of UA in the brain. Our results indicate that the OTs treatment restored MMP, increased MCI and ALDH2 activity, and decreased PC content in ROT-induced rats. Furthermore, we confirmed the presence of UA in the brains of the animals. While its exact contribution to the observed mitochondrial effects remains undetermined, this finding suggests a potential role of the gut-derived metabolite in neuroprotection. Thus, we conclude that OTs administration attenuates mitochondria-related neurotoxicity. We call for further mechanistic studies and the putative contribution of metabolites, including UA, to the demonstrated mitoprotective effect of OTs treatment.
Wojciechowska O, Jourdes M, Andrusiewicz M, Pokrzywa M, Karaźniewicz-Łada M, Jodynis-Liebert J, Teissedre PL, Kujawska M, Biochemistry and biophysics reports
BACKGROUND: Urolithin A (UA) is a metabolite produced by gut bacteria following the consumption of ellagitannin-rich foods. Clinical trials in middle-aged and older adults demonstrated that supplementation with UA improves muscle strength, endurance, and biomarkers of mitochondrial health, suggesting that UA may be an effective ergogenic aid in other populations.
METHODS: In this double-blind, parallel group, placebo-controlled clinical trial (NCT04783207), competitive male distance runners (n = 42, 27.2 ± 1.0 years, 66.4 ± 0.6 mL·kg·min, mean ± SEM) were randomized to consume either 1000 mg·day UA (n = 22) or placebo (PL; n = 20) for 4 weeks during an altitude training camp (~ 1700-2200 m). Physiological outcomes including body composition, hemoglobin mass, running economy, and maximal aerobic capacity ( ) were measured in all subjects at baseline and at the end of the 4-week camp to assess training- and supplementation-induced adaptations. During the camp, a weekly downhill running bout was performed to challenge skeletal muscle, with capillary blood samples collected to assess inflammation (C-reactive protein; CRP) and indirect markers of muscle damage (creatine kinase; CK). A subset of athletes also either completed a 3000 m track time trial (n = 11 PL, n = 11 UA) or had skeletal muscle biopsies taken (n = 9 PL, n = 11 UA) pre/post supplementation to determine the effect of UA on running performance and for exploration of alterations in skeletal muscle proteome and mitochondrial function, respectively.
RESULTS: Running performance (3000 m time trial) was not significantly improved in either treatment group (UA; p = 0.116, PL; p = 0.771), although UA supplementation significantly lowered ratings of perceived exertion (RPE, p = 0.02) and reduced indirect markers of post-exercise muscle damage (CK, total area under the curve p < 0.0001) following the 3000 m time trial compared with PL. Although there was no statistically significant time × treatment interaction for aerobic capacity (p = 0.138), UA supplementation showed a large within-group increase in (5.4 ± 0.9%, 66.4 ± 0.8 to 70.0 ± 1.0 mL·kg·min, p = 0.009, d = - 0.83), with a smaller increase in the PL group (3.6 ± 1.3%, 66.4 ± 0.9 to 68.7 ± 1.0 mL·kg·min, p = 0.098, d = - 0.54). Proteomic screening of skeletal muscle biopsies revealed UA upregulated pathways associated with mitochondria, while downregulating inflammatory pathways. While not statistically significant, UA led to a medium effect for increased markers of mitophagy (d = - 0.74), without changes in mitochondrial function.
CONCLUSIONS: Our results show that 4 weeks of daily UA supplementation facilitates recovery by downregulating inflammatory pathways and indirect markers of muscle damage. However, despite a reduction in rating of exertion and increased aerobic capacity, UA supplementation did not further enhance performance in highly trained male endurance athletes.
Whitfield J, McKay AKA, Tee N, McCormick R, Morabito A, Karagounis LG, Fouassier AM, D'Amico D, Singh A, Burke LM, Hawley JA, Sports medicine (Auckland, N.Z.)
Urolithin A (UA), a metabolite of dietary ellagitannins produced by the gut microbiome, is a potential dual-purpose bioactive compound that may interfere with the shared pathogenic pathways linking colorectal cancer (CRC) and type 2 diabetes mellitus (T2DM). This review summarizes recent preclinical and clinical data on UA's mechanisms, therapeutic potential, and translational challenges. In CRC models, UA promotes G2/M cell cycle arrest, triggers both intrinsic and extrinsic caspase-mediated apoptosis, enhances CD8+ T-cell mitophagy and memory functions, suppresses Wnt/β-catenin signaling, and reduces chemoresistance, especially to 5-FU. For T2DM, UA enhances autophagic flux, mitophagy, insulin signaling, and GLUT4-mediated glucose uptake through the AMPK and PI3K/AKT pathways, reduces fasting glucose and insulin resistance in animal studies, and promotes adipose tissue browning and mitochondrial beta-oxidation. Human biomarker research is limited but indicates positive changes following interventions that increase UA. Future priorities include biomarker-driven, dose-finding trials stratified by metabotype, developing colon-targeted vs. systemic formulations, and testing combinations with chemotherapy and immunotherapy to determine safety and effectiveness.
Joseph V, Hornak S, Kubatka P, Büsselberg D, Nutrients
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