Search Results (127)

Lymphoma continues to pose a serious challenge to global health, underscoring the urgent need for new therapeutic strategies. Recently, the gut microbiome has been shown to play a potential role in regulating immune responses and influencing cancer progression. However, its molecular mechanisms of action in lymphoma remain poorly understood. This study investigates the antiproliferative and apoptotic activities of gut microbiota-derived metabolites, specifically nisin (N) and urolithin B (UB), individually and in combination 7:3 (5750 μM), against the human lymphoma cell line HKB-11. Comprehensive evaluations were performed using Alamar Blue viability assays, combination index (CI) analyses, reactive oxygen species (ROS) quantification, flow cytometry for apoptosis detection, and advanced bottom-up proteomics analyses. N and UB exhibited potent antiproliferative activity, with the 7:3 combination demonstrating strong synergistic effects (CI < 1), significantly enhancing apoptosis (p < 0.01) and ROS production (p < 0.0001) compared to the untreated control. Proteomics analyses revealed substantial alterations in proteins crucial to ribosomal biogenesis, mitochondrial function, cell cycle control, and apoptosis regulation, including a marked downregulation of ribosomal proteins (RPS27; Log₂FC = −3.47) and UBE2N (Log₂FC = −0.60). These findings highlight the potential of N and UB combinations as a novel and practical therapeutic approach for lymphoma treatment, warranting further in vivo exploration and clinical validation. Full article

Cirrhosis remains a significant global health burden, responsible for nearly 4% of annual deaths worldwide. Despite progress in antiviral therapies and public health measures, its prevalence has plateaued, particularly in regions affected by viral hepatitis, alcohol misuse, and metabolic syndrome. This review presents a comprehensive synthesis of the multifactorial drivers of cirrhosis, including hepatocyte injury, liver stellate cell activation, and immune-mediated inflammation. The emphasis is on the central role of metabolic dysfunction, characterized by mitochondrial impairment, altered lipid and glucose metabolism, hormonal imbalance, and systemic inflammation, in exacerbating disease progression. While current therapies may slow the progression of early-stage disease, they are very often ineffective in reversing established fibrosis. Emerging molecular strategies offer promising alternatives by targeting key pathogenic pathways. These include AMPK activators (e.g., metformin, AICAR), FGF21 analogs, and mitochondria-targeted agents (e.g., MitoQ, urolithin A, NAD+ precursors) to restore bioenergetic balance and reduce oxidative stress. Other approaches, such as mesenchymal stem cell therapy, inflammasome inhibition, and hormonal modulation, aim to suppress fibrogenesis and restore liver homeostasis. The integration of systems biology and multi-omics profiling supports patient stratification and precision medicine. This review highlights a shift toward mechanism-based interventions that have the potential to alter cirrhosis outcomes and improve patient survival. Full article

Major Depressive Disorder (MDD) is increasingly linked to disruptions in blood-brain barrier (BBB) integrity, contributing to neuroinflammation and impaired brain homeostasis. While traditional antidepressant therapies often fail to achieve full remission, growing evidence suggests that specific dietary compounds may offer novel avenues for restoring BBB function and improving mental health outcomes. This review explores the potential of selected nutrients—omega-3 fatty acids, vitamin D, sulforaphane, fucoidan, and urolithins—to modulate BBB integrity through anti-inflammatory, antioxidant, and transporter-regulatory mechanisms. These compounds act by reinforcing tight junctions, reducing matrix metalloproteinase activity, and modulating efflux transporters such as P-glycoprotein. Although current evidence is largely preclinical, the mechanistic insights provided in this review support the rationale for integrating nutritional strategies into the management of MDD. Future clinical studies are needed to validate these findings and develop biomarker-driven approaches for targeting the BBB in nutritional interventions for psychiatric disorders. Full article

Lymphoma continues to pose a significant global health burden, highlighting the urgent need for novel therapeutic strategies. Recent advances in microbiome research have identified gut-microbiota-derived metabolites, or postbiotics, as promising candidates in cancer therapy. This study investigates the antiproliferative and mechanistic effects of two postbiotics, Nisin (N) and Urolithin B (UB), individually and in combination, against the human lymphoma cell line HKB-11. Moreover, this study evaluated cytotoxic efficacy and underlying molecular pathways using a comprehensive experimental approach, including the Alamar Blue assay, combination index (CI) analysis, flow cytometry, reactive oxygen species (ROS) quantification, and bottom-up proteomics. N and UB displayed notable antiproliferative effects, with IC₅₀ values of 1467 µM and 87.56 µM, respectively. Importantly, their combination at a 4:6 ratio demonstrated strong synergy (CI = 0.09 at IC₉₅), significantly enhancing apoptosis (p ≤ 0.0001) and modulating oxidative stress. Proteomic profiling revealed significant regulation of key proteins related to lipid metabolism, mitochondrial function, cell cycle control, and apoptosis, including upregulation of COX6C (Log₂FC = 2.07) and downregulation of CDK4 (Log₂FC = −1.26). These findings provide mechanistic insights and underscore the translational potential of postbiotics in lymphoma treatment. Further preclinical and clinical investigations are warranted to explore their role in therapeutic regimens. Full article

Background/Objectives: Urolithin A (UA), a gut-derived metabolite of ellagitannins or ellagic acid, has recently gained attention for its potential benefits to brain health. The present research aimed to assess the antidepressant-like properties of UA in both in vitro and in vivo models and explored the molecular mechanisms underlying these effects. Methods: We investigated the antidepressant effects and mechanisms of UA in a model of corticosterone-induced damage to PC12 cells and in a model of chronic socially frustrating stress. Results: Our results demonstrate that UA treatment (5 and 10 μM) significantly alleviated cellular damage and inflammation in corticosterone (CORT)-treated PC12 cells. Furthermore, UA administration (50 and 100 mg/kg) significantly reduced immobility time in the mouse tail suspension test (TST) and forced swim test (FST), indicating its antidepressant-like activity. Additionally, treatment with UA led to the activation of the cAMP response element-binding protein (CREB)/brain-derived neurotrophic factor (BDNF) signaling cascade and triggered the activation of adenosine monophosphate-activated protein kinase (AMPK) during these processes. Importantly, pretreatment with AMPK-specific inhibitor Compound C abolished UA’s cytoprotective effects in PC12 cells, as well as its behavioral efficacy in the FST and TST, and its neurotrophic effects, highlighting the critical role of AMPK activation in mediating these effects. Furthermore, in the chronic social defeat stress (CSDS) mouse model, UA treatment (50 and 100 mg/kg) significantly alleviated depression-like behaviors, including reduced sucrose preference in the sucrose preference test, increased social avoidance behavior in the social interaction test, and anxiety-like behaviors, including diminished exploration, in the elevated plus maze test, suggesting the antidepressant-like and anxiolytic-like activities of UA. Moreover, UA treatment reversed elevated serum stress hormone levels, hippocampal inflammation, and the decreased AMPK/CREB/BDNF signaling pathway in the hippocampus of CSDS mice. Conclusions: Together, these results provide compelling evidence for UA as a viable dietary supplement or therapeutic option for managing depression. Full article

Urolithin A, which is a natural gut microbial metabolite, exerts multiple beneficial effects upon supplementation, including prolonging lifespan, mitigating diseases, restoring the quality of aged oocytes and alleviating drug toxicity. The study aims to investigate the ovarian protective role of Urolithin A using a neonatal mouse ovarian in vitro culture and chemotherapy model, with a particular focus on its mechanisms for inhibiting primordial follicle activation and mitigating cyclophosphamide (CY) or 4-hydroperoxy (4-HC)-induced follicle apoptosis. The results showed that Urolithin A significantly decreased the number of growing follicles and downregulated the expression of oocyte growth-related genes (Gdf9 and Zp3) and protein (DDX4), as well as Ki-67 and BrdU-positive signals. Further studies revealed that Urolithin A significantly downregulated the levels of phosphorylated Akt and FOXO3a and decreased the percentage of oocytes with FOXO3a nuclear export. Molecular docking showed a strong binding ability between Urolithin A and its downregulated gene Pik3cg. Moreover, Urolithin A significantly decreased CY- and 4-HC-induced increases in cleaved Caspase-3- and PARP1-positive signals. Meanwhile, RNA-seq analysis indicated that Urolithin A significantly downregulated CY-induced expression of DNA damage-related genes (Trp73 and Trim29). In short, Urolithin A inhibits primordial follicle activation by reducing PI3K/Akt signaling reactivity. Furthermore, Urolithin A prevents CY-induced follicle apoptosis. The study provides valuable insights into Urolithin A treatment for chemotherapy-induced infertility. Full article

Periodontitis is an inflammatory disease that affects the periodontal supporting tissues. Its cardinal clinical manifestations encompass gingival inflammation, periodontal pocket formation, and alveolar bone resorption. Urolithin A (UA), a gut microbiota-derived metabolite of ellagitannins, is known for its anti-inflammatory and osseous-protective properties. Nonetheless, the impact of UA on periodontitis remains unknown. To investigate the preventive effect of UA, we employed a lipopolysaccharide (LPS)-induced inflammation model in RAW 264.7 mouse macrophages, a receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation model, and a ligature-induced periodontitis model in mice. The expression of inflammatory factors (tumor necrosis factor-α, TNF-α; interleukin-6, IL-6) was analyzed to assess anti-inflammatory efficacy. Bone loss in mice with periodontitis was assessed through histological and imaging techniques, including haematoxylin and eosin staining to evaluate alveolar bone morphology, Masson’s trichrome staining to visualize collagen fiber distribution, and micro-computed tomography scanning to quantify bone structural parameters. Additionally, we investigated the underlying mechanisms by examining osteoclast activity through tartrate-resistant acid phosphatase staining and the expression levels of proteins RANKL and osteoprotegerin (OPG). We found that UA reduced IL-6 and TNF-α levels in vitro and in vivo, inhibited osteoclast differentiation, and decreased the RANKL/OPG ratio in periodontitis mice. Full article

With the global trend of population aging becoming increasingly pronounced, the incidence of central nervous system (CNS) disorders continues to rise, posing a significant challenge to public health systems worldwide. Currently, many CNS disorders lack effective treatments, prompting researchers to investigate the therapeutic potential of natural compounds. Urolithin A (UA), a gut microbiota-derived metabolite of ellagitannins and ellagic acid, can cross the blood–brain barrier and exhibits a favorable safety profile. This review summarizes the biosynthesis, pharmacokinetic profile, and key biological effects of UA, including its promotion of mitophagy and mitochondrial homeostasis, as well as its anti-inflammatory, antioxidant, anti-senescence, and anti-apoptotic properties. We comprehensively summarize the preclinical evidence demonstrating UA’s therapeutic potential in CNS disorders, such as Alzheimer’s disease, Parkinson’s disease, and stroke. Recent clinical trials involving UA are presented, followed by a thorough analysis of the challenges associated with translating UA-based interventions into clinical practice for CNS disorders. This work aims to support the development of UA-based therapies to improve patient outcomes and address the growing global burden of CNS disorders. Full article

Ellagic acid (EA) is a natural polyphenol found in various fruits, nuts, and mushrooms. It exhibits a variety of biological activities, including potent antioxidant, anti-inflammatory, anti-obesity, and neuroprotective properties. EA exerts hepatoprotective effects through multiple mechanisms, including (1) scavenging reactive oxygen species (ROS) and enhancing endogenous antioxidant defenses (e.g., by activating Nrf2/ARE), (2) modulating inflammatory signaling pathways (e.g., inhibiting NF-κB, TNF-α, and IL-6), and (3) regulating apoptosis (e.g., downregulating the Bax/Bcl-2 ratio) and fibrosis (e.g., inhibiting TGF-β/Smad signaling). Despite its promising preclinical efficacy, the clinical applicability of EA is currently limited by its poor bioavailability. This could potentially be overcome by advanced delivery systems or by directly administering its active microbial metabolites, known as urolithins. EA and its derivatives also modulate the gut microbiota, promoting the growth of beneficial species and reducing gut permeability and hepatic inflammation. Preliminary clinical trials and other emerging evidence suggest that EA may reduce liver inflammation, oxidative stress, and metabolic dysregulation. However, more extensive human studies are needed to confirm its efficacy and safety in managing liver disease. This review highlights the therapeutic potential of EA in the treatment of liver diseases, particularly metabolic-dysfunction-associated steatotic liver disease (MASLD). Full article

Ellagitannins are bioactive phenolic acids found in various fruits, plants, and beverages such as wine and spirits. This review aims to discuss the metabolism, absorption, and some health benefits related to the intestinal activity of these molecules, as well as some supplements developed from them. Ellagitannins are first biodegraded to ellagic acid and then to urolithins, which are more easily absorbed. This process is mediated by specific enzymes and intestinal microbiota. Not all individuals can metabolize ellagitannins into urolithins due to differences in the composition of the intestinal microbiota, resulting in three phenotypes: metabotypes A, B, and 0. In recent decades, ellagitannins and their derivatives (ellagic acid and urolithins) have gained significant attention for their potential benefits against various digestive diseases, including irritable bowel syndrome, peptic ulcers, gastritis, colon cancer, esophageal cancer, and pancreatic cancer. As a result, nutraceutical supplements have been developed to treat these conditions, representing significant and promising applications of these compounds in digestive health. Full article

Cisplatin, a widely used chemotherapeutic agent, is known to induce premature ovarian insufficiency (POI) and infertility in women of reproductive age. Among the contributing factors, cisplatin-induced apoptosis of ovarian granulosa cells is considered a primary driver of ovarian dysfunction; however, the underlying mechanisms remain incompletely understood. In this study, we investigated the cytotoxicity of cisplatin on the granulosa cell line KGN in vitro and explored the associated mechanisms. Our results demonstrate that cisplatin induces KGN cell apoptosis in a dose-dependent manner and impairs mitochondrial function, as evidenced by excessive ROS production, membrane potential collapse, and reduced ATP synthesis. Mitophagy, a key cellular self-protection mechanism that selectively removes damaged mitochondria, was activated following cisplatin treatment, mitigating its detrimental effects on KGN cells. Activation of mitophagy with urolithin A (UA) ameliorated cisplatin-induced mitochondrial dysfunction and apoptosis, whereas inhibition of mitophagy with cyclosporine A (CsA) exacerbated these effects. Furthermore, pretreatment with the clinical drug melatonin significantly enhanced mitophagy, effectively attenuating cisplatin-induced apoptosis in KGN cells. This study proposes a novel therapeutic strategy for patients undergoing tumor chemotherapy, aiming to preserve treatment efficacy while reducing the adverse effects of chemotherapeutic agents on ovarian function, thereby improving patients’ quality of life. Full article

Pomegranate is recognized for its health benefits, primarily due to its polyphenols and metabolites, such as urolithins (Uro-A), produced via colonic fermentation of ellagic acid (EA). These compounds make pomegranate a functional food with the potential to modulate chronic disease risk factors and enhance gut health by modulating microbiota. The aims of this study were (1) to evaluate the effect of in vitro digestion and fermentation mimicking human digestive processes on the total phenolic content (TPC) and the antioxidant capacity of a standardized pomegranate extract (PE), (2) to assess the effect of the digested PE on the functionality of gut microbiota isolated from healthy and diseased subject fecal materials via short-chain fatty acid (SCFA) determination, and (3) to measure Uro-A production using UHPLC Q-Orbitrap HRMS. The in vitro digestion and fermentation processes resulted in a significant increase in the TPC, while the antioxidant capacity was considerably reduced. Following the in vitro digestion process, the TPC increased from 232 ± 16 to 1656 ± 34 g GAE/g of PE. Moreover, the TPC in the fermented samples was calculated as 6139 ± 458 g GAE/g for the microbiota of healthy adults and 8375 ± 1388 g GAE/g for the microbiota of healthy children, compared to 1657 ± 34 g GAE/g for the non-fermented samples. The PE exerted a modulatory effect on gut microbiota functionality, as reflected by an increasing concentration of SCFAs, especially lactic acid. Overall, these data suggest that pomegranate might contribute to gut health and could be a candidate for further studies in view of its possible use as a prebiotic ingredient. Further research, including clinical studies, is needed to confirm these findings and explore the potential application of pomegranate extract as a functional ingredient in nutraceuticals and functional foods aimed at improving gut health. Full article

Both the livestock and biomedical fields require a large supply of high-quality mature oocytes. However, the in vitro maturation (IVM) process often leads to an accumulation of reactive oxygen species (ROS), which can cause defects in oocyte meiosis and embryo development, ultimately compromising oocyte quality. Urolithin A (UA), known for its antioxidant properties, has not been thoroughly investigated for its potential to mitigate the negative effects of oxidative stress during the in vitro culturing of oocytes, and its underlying mechanism is not well understood. In this study, an in vitro oxidative stress model was established using porcine oocytes treated with H₂O₂, followed by exposure to varying concentrations of UA. The results revealed that 30 μM UA significantly improved both the quality of oocyte culture and the developmental potential of the resulting embryos. UA was found to enhance oocyte autophagy, reduce oxidative stress-induced mitochondrial damage, and restore mitochondrial function. Additionally, it lowered ROS and DNA damage levels in the oocytes, maintained proper spindle/chromosome alignment and actin cytoskeleton structure, promoted nuclear maturation, prevented abnormal cortical granule distribution, and supported oocyte cytoplasmic maturation. As a result, UA alleviated oxidative stress-induced defects in oocyte maturation and cumulus cell expansion, thereby improving the developmental potential and quality of parthenogenetic embryos. After supplementation with UA, pig parthenogenetic embryo pluripotency-related genes (Nanog and Sox2) and antiapoptotic genes (Bcl2) were upregulated, while proapoptotic genes (Bax) were downregulated. In conclusion, this study suggests that adding UA during IVM can effectively mitigate the adverse effects of oxidative stress on porcine oocytes, presenting a promising strategy for enhancing their developmental potential in vitro. Full article

This study establishes and validates a novel ultra-high-performance liquid chromatography (UHPLC) method for the determination of urolithin A content in health products, a bioactive compound with potential anti-aging properties. Given the lack of standardized analytical methods for urolithin A in health products, this research addresses a critical gap in quality control. The method employs a methanol–water mobile phase, optimized gradient elution, and a specialized UPLC column (ACQUITY UPLC CSH Fluoro Phenyl) to achieve high resolution and specificity in the separation of urolithin A from its impurities. A variety of diluents, extraction solvents, and extraction times were tested to maximize analyte recovery and stability, with pure methanol yielding the highest recovery rate (over 95%) in 30 min. The method was validated in terms of linearity, sensitivity, repeatability, specificity, and precision. The calibration curve for urolithin A exhibited excellent linearity (r² = 0.9998) over a concentration range of 0.100–10.000 µg/mL. Detection and quantification limits were found to be 0.051 µg/mL and 0.103 µg/mL, respectively. Precision testing revealed an inter-operator RSD of 1.3%, and recovery rates for spiked samples consistently fell within the 98–102% range. The developed method was successfully applied to analyze the urolithin A content in a commercially available health product, demonstrating its practicality for routine quality control. However, this method may currently be affected by the excipient matrix. This research contributes to the establishment of robust, reliable, and high-sensitivity analytical methods for the bioactive compounds found in health products, with significant implications for regulatory compliance and consumer safety. Full article

Background/Objectives: Irritable bowel syndrome (IBS) is a complex disorder affecting 10% of the global population, but the underlying mechanisms remain poorly understood. By integrating multifluid metabolomics, we aimed to identify metabolite markers of IBS in a large population-based cohort. Methods: We included individuals from TwinsUK with and without IBS, ascertained using the Rome III criteria, and analysed serum (232 cases, 1707 controls), urine (185 cases, 1341 controls), and stool (186 cases, 1284 controls) metabolites (Metabolon Inc.). Results: After adjusting for covariates, and multiple testing, 44 unique metabolites (25 novel) were associated with IBS, including lipids, amino acids, and xenobiotics. Androsterone sulphate, a sulfated steroid hormone precursor, was associated with lower odds of IBS in both urine (0.69 [95% confidence interval = 0.56–0.85], p = 2.34 × 10⁻⁴) and serum (0.75 [0.63–0.90], p = 1.54 × 10⁻³. Moreover, suberate (C8-DC) was associated with higher odds of IBS in serum (1.36 [1.15–1.61]; p = 1.84 × 10⁻⁴) and lower odds of IBS in stool (0.76 [0.63–0.91]; p = 2.30 × 10⁻³). On the contrary, 32 metabolites appeared to be fluid-specific, including indole, 13-HODE + 9-HODE, pterin, bilirubin (E,Z or Z,Z), and urolithin. The remaining 10 metabolites were associated with IBS in one fluid with suggestive evidence (p < 0.05) in another fluid. Finally, we identified androgenic signalling, dicarboxylates, haemoglobin, and porphyrin metabolism to be significantly over-represented in individuals with IBS compared to controls. Conclusions: Our results highlight the utility of a multi-fluid approach in IBS research, revealing distinct metabolic signatures across biofluids. Full article