Search Results (177)

Background/Objectives: Hyperuricemia may influence cognitive function, but current evidence remains inconsistent. This study examined the association between hyperuricemia/gout and cognitive impairment through a prospective cohort study and a systematic review of cohort studies. Methods: Data from 1959 Taiwan Biobank participants aged ≥60 years without mild cognitive impairment (MCI) or dementia at baseline were analyzed over a mean follow-up duration of 4.47 years (2012–2021). Cognitive function was assessed using the Mini-Mental State Examination (MMSE). Participants were classified by changes in serum uric acid status from baseline to follow-up, and Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). For the systematic review, cohort studies published up to March 2026 were identified from eight databases. Results: During follow-up, 1013 participants developed incident MCI and 132 developed dementia. Compared with participants who maintained normal serum uric acid levels, those who developed hyperuricemia during follow-up had a significantly lower MCI risk (HR = 0.72, 95% CI = 0.57–0.90), as did those with persistent hyperuricemia (HR = 0.78, 95% CI = 0.64–0.95). No significant association was observed for dementia. The systematic review of five prospective cohort studies comprising 2,261,704 participants showed inconsistent findings with considerable heterogeneity (I² = 96.7%). Conclusions: Rising serum uric acid levels were associated with lower MCI risk, but not dementia. These findings should not be interpreted as support for intentionally increasing serum uric acid levels or withholding urate-lowering therapy. Further long-term studies are needed. Full article

Background/Objectives: Chronic urate nephropathy (CUN), also referred to as gouty nephropathy, represents a severe renal disease primarily precipitated by long-term hyperuricemia (HUA) and gout. However, the precise molecular mechanisms underlying its pathogenesis remain poorly understood. The present study was designed to explore these mechanisms from the perspective of targeted metabolomics. Methods: The HUA mice constructed by urate oxidase (Uox) gene knockout (KO) and their corresponding wild-type controls were employed for the present study. Serum clinical biochemical parameters were determined, and renal histopathological changes were evaluated using hematoxylin-eosin (HE) staining and Masson’s trichrome staining. A targeted metabolomic strategy based on multiple reaction monitoring (MRM) was utilized to profile the renal metabolic landscape of Uox-KO mice, and potential metabolic biomarkers for CUN were identified via multivariate data analysis. Results: Clinical biochemical analysis revealed a significant elevation in serum uric acid, creatinine, and urea nitrogen levels in Uox-KO mice compared with control mice. Histopathological observations confirmed a typical CUN phenotype in Uox-KO mice, characterized by renal tubular vacuolar degeneration and dilatation, desquamation of tubular epithelial cells into the lumen, neutrophil infiltration, glomerular crowding, and renal interstitial fibrosis. Metabolomic analysis identified a total of 291 differentially regulated metabolites in Uox-KO mice relative to control animals. These perturbed metabolites were involved in multiple key biochemical pathways, including amino acid biosynthesis, ABC transporter signaling pathway, purine metabolism, aminoacyl-tRNA biosynthesis, protein digestion and absorption, glycerophospholipid metabolism, and serotonergic synaptic transmission. Notably, pathological parameters, including biochemical measurements and histological observations, were significantly correlated with key differential metabolites associated with CUN progression. Furthermore, eleven differential metabolites (pyroglutamic acid, fructose, riboflavin, dimethyl-L-arginine, glucaric acid, indoxyl sulfate, palmitoylethanolamide, trimethylamine N-oxide, 3-hydroxyanthranilic acid, spermidine, and hippuric acid) were identified as potential metabolic biomarkers for the diagnosis and prognosis of CUN. Conclusions: These findings illustrate that targeted tissue metabolomic analysis constitutes a powerful tool for deciphering the molecular mechanisms of diseases, thus offering novel insights into the pathogenesis of CUN. Full article

Background/Objectives: Hyperuricemia is a metabolic disorder characterized by renal dysfunction and systemic inflammation. While Clematis chinensis Osbeck is traditionally used for gout-related conditions, its chemical basis and precise mechanisms remain poorly understood. This study aimed to characterize the bioactive fraction (CWE-60EF) and elucidate its multi-target regulatory mechanisms against hyperuricemia. Methods: Qualitative and quantitative chemical profiling of CWE-60EF was performed using high-resolution LC-MS/MS. Its anti-hyperuricemic activity was validated using in vitro xanthine oxidase (XOD) inhibition, a zebrafish model, and HK-2 cell injury models. Mechanisms were explored through an integrated approach combining bioinformatics, Mendelian randomization (MR), and molecular docking. Results: A total of 50 compounds, primarily alkaloids and flavonoids (e.g., magnoflorine and phloretin), were characterized in CWE-60EF, and major marker compounds were quantitatively standardized. The fraction significantly inhibited XOD activity and rescued hyperuricemia-associated phenotypes in zebrafish. In HK-2 cells, CWE-60EF suppressed adenosine- and urate-induced cellular injury and the transcriptional expression of pro-inflammatory cytokines (IL-6 and IL-1β). MR analysis provided genetic evidence supporting IL-6 as a causal mediator of gout risk. Integrative analysis revealed that the protective effects of CWE-60EF are mediated through the coordinated regulation of purine metabolism, inflammatory cascades, and urate transporters (URAT1/GLUT9). Conclusions: This study demonstrates that CWE-60EF is a quantitatively standardized bioactive fraction that exerts anti-hyperuricemic, renoprotective, and anti-inflammatory effects by modulating uric acid metabolism and inflammation. By integrating genetic causality with phytochemical validation, our findings provide a novel mechanistic foundation for the traditional application of C. chinensis in hyperuricemic disorders. Full article

This study aimed to optimize the ultrasonic-assisted extraction of polyphenols from Archidendron clypearia and to evaluate their anti-hyperuricemic effects. Polyphenols from medicinal plants have attracted increasing attention due to their potential roles in regulating uric acid metabolism. In this study, single-factor experiments combined with Box–Behnken response surface methodology were employed to optimize extraction conditions, and an entropy weighting method was applied to integrate total polyphenols and Archidendrin I into a comprehensive evaluation index. The bioactivity of the obtained extract was further assessed through in vitro assays and a hyperuricemic mouse model. The optimal extraction conditions were determined to be 50% ethanol, a liquid-to-material ratio of 30, and 31 min of sonication, yielding 175 mg GAE/g DW of total polyphenols and 80.34 mg/g DW of Archidendrin I. The extract exhibited significant xanthine oxidase inhibitory activity, reduced serum uric acid levels, regulated urate transporters (URAT1, GLUT9, and ABCG2), and alleviated renal and hepatic injury in hyperuricemic mice. These findings indicate that the optimized process enables efficient extraction of polyphenols from Archidendron clypearia, and the resulting extract exerts beneficial regulatory effects on uric acid metabolism, highlighting its potential as a natural agent for hyperuricemia management. Full article

Background/Objectives: Asymptomatic hyperuricemia has been associated with increased cardiovascular risk; it is related to factors such as diet, genetic predisposition, and drug-related side effects. Impairment of uric acid control has been associated with the calcineurin inhibitors cyclosporin and tacrolimus, although available studies did not reach the same conclusions. Their widespread use in solid organ transplantation potentially exposes this population to higher cardiovascular risk. This systematic review aimed to assess their role in hyperuricemia risk compared with other immunosuppressive treatments and to clarify potential differences between cyclosporin and tacrolimus. Methods: The search was conducted in MEDLINE and Embase, limited to adult subjects, using the following terms: ((cyclosporin) OR (cyclosporine) OR (tacrolimus) OR (calcineurin inhibitor)) AND ((uric acid) OR (urate) OR (hyperuricemia)) AND ((transplant) OR (transplantation)). We assessed the quality of the studies according to the Critical Appraisal Skills Programme checklist. Results: After screening 639 manuscripts, we selected 36 studies that were relevant to our focus: 28 evaluated kidney transplant patients, while only eight focused on other solid organ transplants. Specifically, 20 studies compared calcineurin inhibitors with other immunosuppressants, while 15 assessed the impact of cyclosporin versus tacrolimus, and one study contributed to both scenarios. The prevalence of hyperuricemia ranged from 30 to 80% among patients receiving calcineurin inhibitors, with a slightly higher prevalence with cyclosporin than with tacrolimus (51–61% vs. 36–42%, respectively). The overall quality of the included studies was generally rated as low to moderate, with only ten studies focusing on uric acid control. Conclusions: Given the heterogeneity and overall quality of the available studies, no definitive conclusions can be drawn. In particular, the comparative effect of cyclosporin and tacrolimus remains uncertain because of conflicting findings across studies. Although calcineurin inhibitors may adversely affect uric acid control in transplant recipients, this association may be influenced by several confounding factors. Full article

Hyperuricemia, a common metabolic disorder characterized by elevated serum uric acid (UA) levels, can lead to severe complications such as gout and renal impairment. Conventional therapies, while effective, are frequently accompanied by significant adverse effects, underscoring the urgent need for safer therapeutic alternatives. Recent evidence identifies the intestine as a novel, pivotal regulator of UA homeostasis, presenting a promising therapeutic axis. This review delineates the intestinal mechanisms governing UA regulation and evaluates the therapeutic potential of natural active substances that target these pathways. We conducted a comprehensive review of recent preclinical studies focusing on intestinal mechanisms involved in UA metabolism, including the roles of gut microbiota, urate transport proteins, intestinal barrier function, and inflammation. Studies evaluating natural active substances—such as polyphenols, polysaccharides, peptides, and plant extracts—were systematically analyzed for their effects on gut-mediated UA regulation. Natural active substances have been shown to effectively alleviate hyperuricemia by modulating gut microbiota, enhancing UA intestinal excretion, reinforcing intestinal barrier function, and suppressing inflammatory pathways. Collectively, these findings demonstrate the multi-target efficacy of natural active substances within the intestines, offering a promising therapeutic strategy that warrants further investigation into nutrition-based intestinal interventions and novel pharmacological treatments for hyperuricemia. Full article

Background: Hyperuricemia (HUA) is a metabolic disorder that severely threatens human health. Chronic uric acid (UA) overload promotes the progression of tubulointerstitial fibrosis (TIF), leading to impaired UA excretion. Our previous studies identified HIPK2 inhibitor XRF-1021, which exhibits robust anti-TIF activity and lowers UA levels in vivo. This study aimed to elucidate its UA-lowering mechanism and therapeutic potential for HUA. Methods: Uricase and xanthine oxidase (XOD) assays were performed to assess effects on UA degradation/production. HEK293T cells transiently expressing UA transporters and gene-knockdown rats were used to evaluate transporter inhibition, while HK-2 cells were analyzed by Western blot. Pharmacokinetics were characterized in rats. Efficacy was tested in potassium oxonate-induced acute HUA rats, diet/adenine-induced chronic HUA quails, and adenine-induced mice with HUA secondary to TIF. Maximum tolerated dose and long-term toxicity were assessed in rats. Results: XRF-1021 neither activated uricase nor inhibited XOD, indicating no direct effect on UA catabolism or synthesis. Instead, XRF-1021 inhibited URAT1 and GLUT9, reducing renal UA reabsorption, while sparing OAT3, OAT4, and ABCG2 activity and upregulating OAT3 and NPT4, suggesting minimal risk of disrupting drug or uremic toxin handling. XRF-1021 showed dose-dependent systemic exposure in rats, lowered serum UA, and provided renal protection in vivo. LD₅₀ values were 2345.4 mg/kg (male) and 1078.9 mg/kg (female), with no obvious toxicity after long-term dosing. Conclusions: XRF-1021 lowers UA by inhibiting URAT1 and GLUT9 to enhance renal UA excretion and provides kidney protection, supporting XRF-1021 as a promising candidate for HUA therapy. Full article

‘Irregular gout’ is an obsolete term that was used in the past to describe both trivial and serious health issues seemingly related to gouty arthritis. This article looks back at what physicians such as George Cheyne, William Oliver, William Cullen and William Heberden thought about ‘irregular gout’. It examines to what degree the concept is still relevant, knowing what we now know about uric acid and the local and systemic inflammatory effects of urate crystal formation. In parallel, the article traces the trajectory from Cullen’s ‘asthenic gout’ to nineteenth century ‘uric acid poisoning’ and thence to possible hidden consequences of asymptomatic hyperuricaemia. ‘Irregular gout’ in its various guises has greatly influenced both orthodox and unorthodox treatments over the years. Although the term is no longer used, the concept is by no means dead. Full article

Hyperuricemia is a metabolic disorder characterized by elevated serum uric acid levels and is increasingly linked to alterations in intestinal mucosal condition and gut microbiota composition. Probiotics have been proposed as safe, non-pharmacological approaches for managing hyperuricemia, but strain-specific evidence remains limited. This study aimed to evaluate the anti-hyperuricemic potential of Limosilactobacillus reuteri MBHC10138, isolated from human breast milk, and to examine its association with purine metabolism–related parameters, renal morphological features, intestinal barrier-associated markers, and gut microbiota composition. In vitro, MBHC10138 effectively degraded purine nucleosides that are metabolized into uric acid, suggesting its potential to reduce uric acid production in the host. In a mouse model of diet- and oxonate-induced hyperuricemia, oral administration of MBHC10138 significantly lowered serum uric acid levels to a level comparable with allopurinol treatment, while improving renal morphology. Histological and molecular analyses demonstrated restoration of the tight junction proteins zonula occludens-1 and occludin, indicative of enhanced intestinal barrier integrity. Furthermore, MBHC10138 administration modulated the gut microbiota by restoring microbial α-diversity and significantly increasing the relative abundances of the Clostridia vadinBB60 group and Oscillospiraceae, taxa associated with butyrate production, compared with the allopurinol-treated group. Collectively, these findings indicate that MBHC10138 exerts dual actions against hyperuricemia and intestinal barrier dysfunction through the regulation of purine metabolism, promotion of renal urate excretion, and modulation of gut microbial composition. MBHC10138 may thus represent a promising probiotic candidate for the prevention and adjunctive management of hyperuricemia-related metabolic disorders. Full article

Background/Objectives: Hyperuricemia (HUA) is the second most common metabolic disease in China (24.5% in males, 3.6% in females), which can induce multiple complications such as gout and diabetes. Existing urate-lowering drugs have significant hepatorenal toxicity, necessitating safe lifestyle interventions. Electrolyzed alkaline water (EAW) as daily drinking water has shown preliminary effectiveness, but it lacks randomized controlled evidence and mechanistic studies at the microbiome–metabolome interface. Methods: We conducted a 12-week randomized controlled trial in 40 adults aged 18–65 years with elevated serum uric acid (SUA). Participants consumed either 1.5 L/day of EAW (pH 8.5–9.5) or purified water (pH 7.0). Clinical indicators, quality of life (SF-36), gut microbiota, and gut metabolomics were comprehensively assessed to evaluate intervention efficacy and explore potential mechanisms. Results: After 12 weeks, the EAW group exhibited a larger reduction in serum uric acid than the control group, along with improvements in selected physical health-related quality-of-life measures. Modest differences in gut microbial composition were observed between groups. Metabolomic analyses identified group-level differences in metabolites enriched in pathways related to purine metabolism and other urate-associated metabolic processes. Conclusions: This pilot randomized controlled trial suggests that consumption of EAW is associated with a modest reduction in serum uric acid. Exploratory multi-omics analyses indicate concurrent changes in gut microbiota and metabolic profiles. These findings support further investigation of electrolyzed alkaline water as a potential adjunctive, non-pharmacological option for hyperuricemia in larger and longer-term studies. Ethics: This trial was registered with the Chinese Clinical Trial Registry under the identifier ChiCTR2500100190. Ethical approval for the present study was granted by the Nankai University Institutional Review Board (NKUIRB2025001, 23 January 2025). Full article

Background: d-Limonene (LIM) is a food-derived monoterpenoid phytocompound predominantly found in citrus peels, endowed with potent antioxidant and anti-inflammatory properties, and has been reported to inhibit xanthine oxidase (XO) activity in vitro. This study investigated the dose-sparing efficacy of this dietary bioactive compound in combination with low-dose allopurinol (ALP) using a dual rat model combining potassium oxonate (PO)-induced hyperuricemia and monosodium urate (MSU)-triggered gouty arthritis, thereby capturing both metabolic and inflammatory dimensions of gout. Methods: Female Wistar rats were PO-primed and MSU-challenged, then treated with LIM (50 mg/kg), ALP (5 or 10 mg/kg), or LIM + ALP. Outcomes included paw thickness, dysfunction and inflammation indices, serum uric acid, urea, creatinine, AST/ALT, cytokines (IL-1β, TNF-α, IL-6), oxidative stress markers (MDA, SOD, catalase, GSH), and NLRP3 immunoreactivity, supported by radiographic and histopathological analyses. Data were analyzed by one-way ANOVA with Tukey’s post hoc test. Results: LIM improved clinical and biochemical outcomes versus monotherapies. However, LIM + low-dose ALP exhibited the greatest overall efficacy. On Day 30, paw thickness was significantly lower with LIM + ALP than with LIM alone (3.25 ± 0.31 vs. 3.98 ± 0.72 mm; p < 0.001). Serum uric acid and hepatic transaminases declined most with the combination (p < 0.0001 vs. LIM), accompanied by improved renal indices (p < 0.001). Pro-inflammatory cytokines were markedly reduced, NLRP3 immunostaining was minimal, and oxidative balance shifted toward homeostasis (↓ MDA; ↑ SOD, catalase, GSH). Radiographic and histological evaluations corroborated attenuation of joint inflammation and tissue damage. Conclusions: In the PO + MSU gout model, co-administration of the food-derived compound LIM with low-dose ALP achieved additive, dose-sparing benefits across metabolic, inflammatory, and histological endpoints. While in vivo XO activity was not directly assessed, the findings are consistent with XO-pathway modulation, NLRP3–IL-1β suppression, and redox restoration. These results highlight the potential of dietary bioactives such as d-Limonene to complement standard urate-lowering therapy, warranting further pharmacokinetic and safety validation. Full article

This study presents the phenotypic characterization and genomic mining of uric acid catabolism genes in Lactiplantibacillus plantarum YC, a novel food-grade lactic acid bacterium isolated from traditional fermented vegetables with potent uric acid-lowering activity. YC is non-hemolytic, catalase- and gelatinase-negative, exhibits strong adhesion and broad antibacterial activity, and degrades 29.22% of uric acid in vitro, along with complete (100%) degradation of inosine and guanosine. Whole-genome sequencing revealed a 3,214,448 bp chromosome encoding 3026 protein-coding genes. Comparative genomics-based functional annotation highlighted abundant CAZy-related genes and antimicrobial factors, including lysozyme and monooxygenase. Crucially, genomic mining identified a complete uric acid degradation gene cluster, comprising pucK (uric acid permease), hpxO (uric acid hydroxylase), eight copies of hiuH (5-hydroxyisourate hydrolase), allB (allantoinase), and purine nucleoside transport/metabolism genes (rihA, rihB, rihC, pbuG). This work provides the first comparative genomic insight into the genetic architecture and distribution of uric acid metabolism in L. plantarum, elucidating YC’s dual urate-lowering mechanism and delivering key molecular markers for developing enzyme-based functional foods and microbial therapeutics against hyperuricemia. Full article

Gout is an inflammatory arthritis triggered by monosodium urate crystal deposition, especially in obese patients. However, distinctions between the characteristics of obese and non-obese patients with gout remain unclear. We aimed to investigate the clinical differences by body mass index (BMI) with gout. We conducted a single-center retrospective cross-sectional study of 269 patients with gout from March 2020 to May 2024. Patients were classified into two groups: underweight/normal BMI and overweight/obesity. Baseline demographics, laboratory data, and clinical outcomes were compared between these groups. Stepwise logistic regression analysis was performed to identify predictors of underweight/normal BMI in gout patients. The underweight/normal BMI group included 35 patients (13.0%), characterized by older age, a higher proportion of females, and a lower prevalence of hypertension and alcohol consumption. This group also demonstrated lower uric acid, lipid profile, and alanine aminotransferase (ALT) levels but had a higher erythrocyte sedimentation rate. Logistic regression analysis identified female sex (odds ratio [OR] 3.831, 95% confidence interval [CI] 1.254–11.705, p = 0.018), presence of hypertension (OR 0.367, 95% CI 0.166–0.809, p = 0.013), total cholesterol (OR 0.990, 95% CI 0.982–0.999, p = 0.031), and ALT (OR 0.967, 95% CI 0.941–0.995, p = 0.019) as significant predictors of underweight/normal BMI gout. Understanding these characteristics may improve the identification of underweight/normal BMI subgroups, leading to improved approaches for gout management. Full article

Background: Dotinurad (DOT) has demonstrated beneficial metabolic effects in preclinical models as a selective uric acid reabsorption inhibitor. However, its clinical impact on steatotic liver disease (SLD) with hyperuricemia (HU-SLD) remains unclear. Methods: This observational pilot study evaluated 33 patients with HU-SLD (Metabolic dysfunction-associated steatotic liver disease: n = 20; Metabolic dysfunction-associated alcohol-related liver disease: n = 1; Alcohol-related liver disease: n = 12) treated with DOT for at least 6 months. Laboratory parameters were assessed at baseline and at 6 months. The primary outcomes were changes in serum uric acid levels, hepatobiliary function markers, and renal function markers. Results: DOT significantly reduced serum uric acid levels from 8.4 (7.7–9.0) to 6.0 (5.9–6.8) mg/dL at 6 months (p < 0.001). Regarding hepatobiliary markers, gamma-glutamyl transferase decreased from 47 (30–78) to 43 (27–54) U/L (p = 0.042) and total bilirubin decreased from 0.6 (0.5–1.0) to 0.6 (0.4–0.7) mg/dL (p = 0.023). Significant but modest improvements in renal function were also observed, with serum creatinine decreasing from 1.1 (0.9–1.3) to 1.0 (0.9–1.1) mg/dL (p = 0.010) and estimated glomerular filtration rate increasing from 55.6 (44–67.3) to 56.6 (48.8–71.5) mL/min/1.73 m² (p = 0.007). No significant changes were observed for aspartate aminotransferase, alanine aminotransferase, fibrosis-related markers, lipid profiles, or glycemic markers. Moreover, no treatment discontinuations or adverse events were recorded during the study period. Conclusions: DOT effectively reduced serum uric acid and modestly improved renal and hepatobiliary parameters in HU-SLD without any patient-reported complications. These real-world findings support the potential of DOT as a well-tolerated therapeutic option beyond urate lowering and warrant further investigation in larger, controlled studies. Full article

Type 2 diabetes and gout are both common metabolic disorders that frequently occur together. Research indicates that disturbances in intracellular calcium balance may be a key molecular factor linking the development of these two diseases. Calcium signaling disturbances promote the synergistic progression of both diseases through multiple pathways: In pancreatic β-cells, endoplasmic reticulum (ER) calcium imbalance triggers ER stress, mitochondrial dysfunction, and apoptosis, autophagy, and pyroptosis, leading to impaired insulin secretion. Concurrently, calcium overload exacerbates insulin resistance by disrupting insulin signal transduction in peripheral tissues, while hyperinsulinemia further inhibits uric acid excretion through activation of the renal URAT1 transporter, creating a vicious cycle. Additionally, calcium homeostasis dysregulation activates the NLRP3 inflammasome and promotes the release of pro-inflammatory cytokines, aggravating chronic low-grade inflammation, which further deteriorates β-cell function and peripheral metabolic disorders, collectively driving the pathological link between type 2 diabetes and gout. Although calcium channel modulators show potential in improving β-cell function and reducing inflammation, their clinical application faces challenges such as tissue-specific effects and a lack of high-quality clinical trials. We propose that intracellular calcium dysregulation serves as a central pathological amplifier in the diabetes–gout nexus. Future research on targeted calcium signaling interventions, guided by this integrative concept, may help overcome the therapeutic challenges in managing type 2 diabetes complicated by gout. Full article