A widely distributed gene cluster compensates for uricase loss in hominids.

Approximately 15% of US adults have circulating levels of uric acid above its solubility limit, which is causally linked to the disease gout. In most mammals, uric acid elimination is facilitated by the enzyme uricase. However, human uricase is a pseudogene, having been inactivated early in hominid evolution. Though it has long been known that uric acid is eliminated in the gut, the role of the gut microbiota in hyperuricemia has not been studied. Here, we identify a widely distributed bacterial gene cluster that encodes a pathway for uric acid degradation. Stable isotope tracing demonstrates that gut bacteria metabolize uric acid to xanthine or short chain fatty acids. Ablation of the microbiota in uricase-deficient mice causes severe hyperuricemia, and anaerobe-targeted antibiotics increase the risk of gout in humans. These data reveal a role for the gut microbiota in uric acid excretion and highlight the potential for microbiome-targeted therapeutics in hyperuricemia.

Physiologic Medium Rewires Cellular Metabolism and Reveals Uric Acid as an Endogenous Inhibitor of UMP Synthase.

A complex interplay of environmental factors impacts the metabolism of human cells, but neither traditional culture media nor mouse plasma mimic the metabolite composition of human plasma. Here, we developed a culture medium with polar metabolite concentrations comparable to those of human plasma (human plasma-like medium [HPLM]). Culture in HPLM, relative to that in traditional media, had widespread effects on cellular metabolism, including on the metabolome, redox state, and glucose utilization. Among the most prominent was an inhibition of de novo pyrimidine synthesis-an effect traced to uric acid, which is 10-fold higher in the blood of humans than of mice and other non-primates. We find that uric acid directly inhibits uridine monophosphate synthase (UMPS) and consequently reduces the sensitivity of cancer cells to the chemotherapeutic agent 5-fluorouracil. Thus, media that better recapitulates the composition of human plasma reveals unforeseen metabolic wiring and regulation, suggesting that HPLM should be of broad utility.

Renal NF-κB activation impairs uric acid homeostasis to promote tumor-associated mortality independent of wasting.

Tumor-induced host wasting and mortality are general phenomena across species. Many groups have previously demonstrated endocrinal impacts of malignant tumors on host wasting in rodents and Drosophila. Whether and how environmental factors and host immune response contribute to tumor-associated host wasting and survival, however, are largely unknown. Here, we report that flies bearing malignant yki3SA-gut tumors exhibited the exponential increase of commensal bacteria, which were mostly acquired from the environment, and systemic IMD-NF-κB activation due to suppression of a gut antibacterial amidase PGRP-SC2. Either gut microbial elimination or specific IMD-NF-κB blockade in the renal-like Malpighian tubules potently improved mortality of yki3SA-tumor-bearing flies in a manner independent of host wasting. We further indicate that renal IMD-NF-κB activation caused uric acid (UA) overload to reduce survival of tumor-bearing flies. Therefore, our results uncover a fundamental mechanism whereby gut commensal dysbiosis, renal immune activation, and UA imbalance potentiate tumor-associated host death.

Wearable Hydrogel SERS Chip Utilizing Plasmonic Trimers for Uric Acid Analysis in Sweat.

Uric acid is typically measured through blood tests, which can be inconvenient and uncomfortable for patients. Herein, we propose a wearable surface-enhanced Raman scattering (SERS) chip, incorporating a hydrogel membrane with integrated plasmonic trimers, for noninvasive monitoring of uric acid in sweat. The plasmonic trimers feature sub 5 nm nanogaps, generating strong electromagnetic fields to boost the Raman signal of surrounding molecules. Simultaneously, the hydrogel membrane pumps sweat through these gaps, efficiently capturing sweat biomarkers for SERS detection. The chip can achieve saturation adsorption of sweat within 5 min, eliminating variations in individual sweat production rates. Dynamic SERS tracking of uric acid and lactic acid levels during anaerobic exercise reveals a temporary suppression of uric acid metabolism, likely due to metabolic competition with lactic acid. Furthermore, long-term monitoring correlates well with blood test results, confirming that regular exercise helps reduce serum uric acid levels and supporting its potential in managing hyperuricemia.

Polyvinylpyrrolidone-Coated Cubic Hollow Nanocages of PdPt3 and PdIr3 as Highly Efficient Self-Cascade Uricase/Peroxidase Mimics.

Uricase-catalyzed uric acid (UA) degradation has been applied for hyperuricemia therapy, but this medication is limited by H2O2 accumulation, which can cause oxidative stress of cells, resulting in many other health issues. Herein, we report a robust cubic hollow nanocage (HNC) system based on polyvinylpyrrolidone-coated PdPt3 and PdIr3 to serve as highly efficient self-cascade uricase/peroxidase mimics to achieve the desired dual catalysis for both UA degradation and H2O2 elimination. These HNCs have hollow cubic shape with average wall thickness of 1.5 nm, providing desired synergy to enhance catalyst's activity and stability. Density functional theory calculations suggest the PdIr3 HNC surface tend to promote OH*/O* desorption for better peroxidase-like catalysis, while the PdPt3 HNC surface accelerates the UA oxidation by facilitating O2-to-H2O2 conversion. The dual catalysis power demonstrated by these HNCs in cell studies suggests their great potential as a new type of nanozyme for treating hyperuricemia.

Lipidomics and metabolomics investigation into the effect of DAG dietary intervention on hyperuricemia in athletes.

The occurrence of hyperuricemia (HUA; elevated serum uric acid) in athletes is relatively high despite that exercise can potentially reduce the risk of developing this condition. Although recent studies have shown the beneficial properties of DAG in improving overall metabolic profiles, a comprehensive understanding of the effect of DAG in modulating HUA in athletes is still lacking. In this study, we leveraged combinatorial lipidomics and metabolomics to investigate the effect of replacing TAG with DAG in the diet of athletes with HUA. A total of 1,074 lipids and metabolites from 94 classes were quantitated in serum from 33 athletes, who were categorized into responders and non-responders based on whether serum uric acid levels returned to healthy levels after the DAG diet intervention. Lipidomics and metabolomics analyses revealed lower levels of xanthine and uric acid in responders, accompanied by elevated plasmalogen phosphatidylcholines and diminished acylcarnitine levels. Our results highlighted the mechanisms behind how the DAG diet circumvented the risk and effects associated with high uric acid via lowered triglycerides at baseline influencing the absorption of DAG resulting in a decline in ROS and uric acid production, increased phospholipid levels associated with reduced p-Cresol metabolism potentially impacting on intestinal excretion of uric acid as well as improved ammonia recycling contributing to decreased serum uric acid levels in responders. These observed alterations might be suggestive that successful implementation of the DAG diet can potentially minimize the likelihood of a potentially vicious cycle occurring in high uric acid, elevated ROS, and impaired mitochondrial metabolism environment.

SVCT2/SLC23A2 is a sodium-dependent urate transporter: functional properties and practical application.

Urate transporters play a pivotal role in urate handling in the human body, but the urate transporters identified to date do not account for all known molecular processes of urate handling, suggesting the presence of latent machineries. We recently showed that a urate transporter SLC2A12 is also a physiologically important exporter of ascorbate (the main form of vitamin C in the body) that would cooperate with an ascorbate importer, sodium-dependent vitamin C transporter 2 (SVCT2). Based on the dual functions of SLC2A12 and cooperativity between SLC2A12 and SVCT2, we hypothesized that SVCT2 might be able to transport urate. To test this proposal, we conducted cell-based analyses using SVCT2-expressing mammalian cells. The results demonstrated that SVCT2 is a novel urate transporter. Vitamin C inhibited SVCT2-mediated urate transport with a half-maximal inhibitory concentration of 36.59 µM, suggesting that the urate transport activity may be sensitive to physiological ascorbate levels in blood. Similar results were obtained for mouse Svct2. Further, using SVCT2 as a sodium-dependent urate importer, we established a cell-based urate efflux assay that will be useful for identification of other novel urate exporters as well as functional characterization of nonsynonymous variants of already-identified urate exporters including ATP-binding cassette transporter G2. While more studies will be needed to elucidate the physiological impact of SVCT2-mediated urate transport, our findings deepen understanding of urate transport machineries.

Raising serum uric acid with a uricase inhibitor worsens PKD in rat and mouse models.

Humans are predisposed to gout because they lack uricase that converts uric acid to allantoin. Rodents have uricase, resulting in low basal serum uric acid. A uricase inhibitor raises serum uric acid in rodents. There were two aims of the study in polycystic kidney disease (PKD): 1) to determine whether increasing serum uric acid with the uricase inhibitor, oxonic acid, resulted in faster cyst growth and 2) to determine whether treatment with the xanthine oxidase inhibitor, oxypurinol, reduced the cyst growth caused by oxonic acid. Orthologous models of human PKD were used: PCK rats, a polycystic kidney and hepatic disease 1 (Pkhd1) gene model of autosomal recessive PKD (ARPKD) and Pkd1RC/RC mice, a hypomorphic Pkd1 gene model. In PCK rats and Pkd1RC/RC mice, oxonic acid resulted in a significant increase in serum uric acid, kidney weight, and cyst index. Mechanisms of increased cyst growth that were investigated were proinflammatory cytokines, the inflammasome, and crystal deposition in the kidney. Oxonic acid resulted in an increase in proinflammatory cytokines in the serum and kidney in Pkd1RC/RC mice. Oxonic acid did not cause activation of the inflammasome or uric acid crystal deposition in the kidney. In Pkd1RC/RC male and female mice analyzed together, oxypurinol decreased the oxonic acid-induced increase in cyst index. In summary, increasing serum uric acid by inhibiting uricase with oxonic acid results in an increase in kidney weight and cyst index in PCK rats and Pkd1RC/RC mice. The effect is independent of inflammasome activation or crystal deposition in the kidney.NEW & NOTEWORTHY This is the first reported study of uric acid measurements and xanthine oxidase inhibition in polycystic kidney disease (PKD) rodents. Raising serum uric acid with a uricase inhibitor resulted in increased kidney weight and cyst index in Pkd1RC/RC mice and PCK rats, elevated levels of proinflammatory cytokines in the serum and kidney in Pkd1RC/RC mice, and no uric acid crystal deposition or activation of the caspase-1 inflammasome in the kidney.

Plasma albumin, bilirubin, and uric acid and the subsequent risk of cancer: a case-cohort study in the Japan Public Health Center-based Prospective Study.

Several epidemiologic studies have investigated the circulating levels of albumin, bilirubin, and uric acid (UA) in relation to cancer risk; however, they have provided equivocal evidence. In this prospective case-cohort study, we measured the plasma levels of albumin, bilirubin, and UA and investigated their association with cancer incidence in 3584 case patients and 4270 randomly selected participants with a median follow-up of 15.8 years. The adjusted hazard ratios (HRs) and 95% CIs of total cancer for the highest quartile (Q4) versus lowest quartile (Q1) was 0.77 (95% CI, 0.67-0.90; P <.001 for trend) for albumin. This association was attenuated after excluding liver cancer cases with lower plasma albumin levels. Plasma bilirubin levels were positively related to liver cancer but inversely to total cancer after excluding liver cancer with, for Q4 versus Q1, an adjusted HR of 0.86 (95% CI, 0.74-0.99; P = .015 for trend). Plasma UA levels were not dose-responsively associated with total cancer risk. Higher plasma bilirubin levels were associated with a decreased risk of total cancer after excluding liver cancer, which is likely attributed to the antioxidant properties of bilirubin.

Controversies and practical management of patients with gout and chronic kidney disease.

Uric acid is a toxin retained with advancing kidney disease. Clinical manifestations of hyperuricemia include gout and systemic inflammation that are associated with increased risk of cardiovascular mortality. As many as one-third of all patients with chronic kidney disease have a history of gout, yet <25% of these patients are effectively treated to target serum urate levels of ≤6 mg/dl. A major reason for ineffective management of gout and hyperuricemia is the complexity in managing these patients, with some medications contraindicated and others requiring special dosing, potential drug interactions, and other factors. Consequently, many nephrologists do not primarily manage gout despite it being a common complication of chronic kidney disease, leaving management to the primary physician or rheumatologist. We believe that kidney specialists should consider gout as a major complication of chronic kidney disease and actively manage it in their patients. Here, we present insights from nephrologists and rheumatologists for a team approach to gout management that includes the nephrologist.

Retinol dehydrogenase 12 (RDH12) knock out may cause hyperuricemia phenotype in mice.

Hyperuricemia is a chronic metabolic disease caused by purine metabolism disorder. And several gene loci and transporter proteins that associated with uric acid transport functions have been identified. Retinol Dehydrogenase 12 (RDH12), recognized for its role in safeguarding photoreceptors, and our study investigated the potential impact of Rdh12 mutations on other organs and diseases, particularly hyperuricemia. We assessed Rdh12 mRNA expression levels in various tissues and conducted serum biochemical analyses in Rdh12-/- mice. Compared with the wild type, significant alterations in serum uric acid levels and kidney-related biochemical indicators have been revealed. Then further analysis, including quantitative RT-PCR of gene expression in the liver and kidney, highlighted variations in the expression levels of specific genes linked to hyperuricemia. And renal histology assessment exposed mild pathological lesions in the kidneys of Rdh12-/- mice. In summary, our study suggests that Rdh12 mutations impact not only retinal function but also contribute to hyperuricemia and renal disease phenotypes in mice. Our finding implies that individuals with Rdh12 mutations may be prone to hyperuricemia and gout, emphasizing the significance of preventive measures and regular examinations in daily life.

Investigating the nexus of metabolic syndrome, serum uric acid, and dementia risk: a prospective cohort study.

BACKGROUND: The global dementia prevalence is surging, necessitating research into contributing factors. We aimed to investigate the association between metabolic syndrome (MetS), its components, serum uric acid (SUA) levels, and dementia risk. METHODS: Our prospective study comprised 466,788 participants without pre-existing MetS from the UK Biobank. We confirmed dementia diagnoses based on the ICD-10 criteria (F00-03). To evaluate the dementia risk concerning MetS, its components, and SUA levels, we applied Cox proportional hazards models, while adjusting for demographic factors. RESULTS: Over a median follow-up of 12.7 years, we identified 6845 dementia cases. Individuals with MetS had a 25% higher risk of all-cause dementia (hazard ratio [HR] = 1.25, 95% confidence interval [CI] = 1.19-1.31). The risk increased with the number of MetS components including central obesity, dyslipidemia for high-density lipoprotein (HDL) cholesterol, hypertension, hyperglycemia, and dyslipidemia for triglycerides. Particularly for those with all five components (HR = 1.76, 95% CI = 1.51-2.04). Dyslipidemia for HDL cholesterol, hypertension, hyperglycemia, and dyslipidemia for triglycerides were independently associated with elevated dementia risk (p < 0.01). MetS was further linked to an increased risk of all-cause dementia (11%) and vascular dementia (VD, 50%) among individuals with SUA levels exceeding 400 µmol/L (all-cause dementia: HR = 1.11, 95% CI = 1.02-1.21; VD: HR = 1.50, 95% CI = 1.28-1.77). CONCLUSIONS: Our study provides robust evidence supporting the association between MetS, its components, and dementia risk. These findings emphasize the importance of considering MetS and SUA levels in assessing dementia risk, offering valuable insights for prevention and management strategies.

Associations of serum uric acid variability with neuroimaging metrics and cognitive decline: a population-based cohort study.

BACKGROUND: The relationship between variation in serum uric acid (SUA) levels and brain health is largely unknown. This study aimed to examine the associations of long-term variability in SUA levels with neuroimaging metrics and cognitive function. METHODS: This study recruited 1111 participants aged 25-83 years from a multicenter, community-based cohort study. The SUA concentrations were measured every two years from 2006 to 2018. We measured the intraindividual SUA variability, including the direction and magnitude of change by calculating the slope value. The associations of SUA variability with neuroimaging markers (brain macrostructural volume, microstructural integrity, white matter hyperintensity, and the presence of cerebral small vessel disease) and cognitive function were examined using generalized linear models. Mediation analyses were performed to assess whether neuroimaging markers mediate the relationship between SUA variation and cognitive function. RESULTS: Compared with the stable group, subjects with increased or decreased SUA levels were all featured by smaller brain white matter volume (beta = - 0.25, 95% confidence interval [CI] - 0.39 to - 0.11 and beta = - 0.15, 95% CI - 0.29 to - 0.02). Participants with progressively increased SUA exhibited widespread disrupted microstructural integrity, featured by lower global fractional anisotropy (beta = - 0.24, 95% CI - 0.38 to - 0.10), higher mean diffusivity (beta = 0.16, 95% CI 0.04 to 0.28) and radial diffusivity (beta = 0.19, 95% CI 0.06 to 0.31). Elevated SUA was also associated with cognitive decline (beta = - 0.18, 95% CI - 0.32 to - 0.04). White matter atrophy and impaired brain microstructural integrity mediated the impact of SUA increase on cognitive decline. CONCLUSIONS: It is the magnitude of SUA variation rather than the direction that plays a critical negative role in brain health, especially for participants with hyperuricemia. Smaller brain white matter volume and impaired microstructural integrity mediate the relationship between increased SUA level and cognitive function decline. Long-term stability of SUA level is recommended for maintaining brain health and preventing cognitive decline.

Can uric acid affect the immune microenvironment in bladder cancer? A single-center multi-omics study.

Metabolic abnormalities are one of the important factors in bladder cancer (BCa) progression and microenvironmental disturbance. As an important product of purine metabolism, uric acid's (UA) role in BCa metabolism and immunotherapy remains unclear. In this study, we conducted a retrospective analysis of a cohort comprising 39 BCa patients treated with PD-1 and 169 patients who underwent radical cystectomy at Shanghai Tenth People's Hospital. Kaplan-Meier curves and Cox regression analysis showed that the prognosis of patients with high UA is worse (p = 0.007), and high UA is an independent risk factor for cancer specific survival in patients with BCa (p = 0.025). We established a hyperuricemia mouse model with BCa subcutaneous xenografts in vivo. The results revealed that the subcutaneous tumors of hyperuricemia mice had a greater weight and volume in comparison with the control group. Through flow cytometric analysis, the proportion of CD8+ and CD4+ T cells in these subcutaneous tumors was seen to decline significantly. We also evaluated the relationship of UA and BCa by muti-omic analysis. UA related genes were significantly increased in the CD8+ T cell of non-responders to immunotherapy by single-cell sequencing. An 11-gene UA related signature was constructed and the risk score negatively correlated with various immune cells and immune checkpoints. Finally, a nomogram was established using a UA related signature to forecast the survival rate of patients with BCa. Collectively, this study demonstrated that UA was an independent prognostic biomarker for BCa and was associated with worse immunotherapy response.

Alkaline Water: Help or Hype for Uric Acid and Cystine Urolithiasis?

PURPOSE: The consumption of alkaline water, water with an average pH of 8 to 10, has been steadily increasing globally as proponents claim it to be a healthier alternative to regular water. Urinary alkalinization therapy is frequently prescribed in patients with uric acid and cystine urolithiasis, and as such we analyzed commercially available alkaline waters to assess their potential to increase urinary pH. MATERIALS AND METHODS: Five commercially available alkaline water brands (Essentia, Smart Water Alkaline, Great Value Hydrate Alkaline Water, Body Armor SportWater, and Perfect Hydration) underwent anion chromatography and direct chemical measurements to determine the mineral contents of each product. The alkaline content of each bottle of water was then compared to that of potassium citrate (the gold standard for urinary alkalinization) as well as to other beverages and supplements used to augment urinary citrate and/or the urine pH. RESULTS: The pH levels of the bottled alkaline water ranged from 9.69 to 10.15. Electrolyte content was minimal, and the physiologic alkali content was below 1 mEq/L for all brands of alkaline water. The alkali content of alkaline water is minimal when compared to common stone treatment alternatives such as potassium citrate. In addition, several organic beverages, synthetic beverages, and other supplements contain more alkali content than alkaline water, and can achieve the AUA and European Association of Urology alkali recommendation of 30 to 60 mEq per day with ≤ 3 servings/d. CONCLUSIONS: Commercially available alkaline water has negligible alkali content and thus provides no added benefit over tap water for patients with uric acid and cystine urolithiasis.

Longitudinal analysis of serum urate in prediabetic phase.

OBJECTIVES: Despite the well-established association between prediabetes and hyperuricaemia, knowledge about serum urate (SU) trends during the prediabetic phase is limited. Therefore, we aimed to assess the longitudinal changes of SU in individuals with prediabetes. METHODS: Individuals with prediabetes, defined by initial haemoglobin A1c (HbA1c) levels between 5.7% and 6.4%, were identified using electronic health records from an academic health system (2007-2022). We required at least one SU test before and after the prediabetes diagnosis. The primary outcome was the longitudinal SU trends during the follow-up period, estimated with a multivariable mixed-effects model. Patients were censored at diabetes onset. Marginal effects of covariates on SU changes were estimated. Subsequent analyses examined SU variations in subgroups stratified by age, sex, body mass index (BMI), HbA1c, estimated glomerular filtration rate (eGFR) and metformin use. RESULTS: Out of 25 526 individuals with prediabetes, 1,521 met the SU cohort requirements, contributing to 6,832 SU observations. At baseline, median age was 63 years and 40% were female. Median values were SU 6.3 mg/dl, HbA1c 5.9% and BMI 30 kg/m2. Median follow-up was 7.4 years. Older age, male sex, greater BMI, and higher HbA1c were significant predictors of increased longitudinal SU levels. Individuals with a BMI ≥30 kg/m2 exhibited higher SU levels compared with those with lower BMI values. CONCLUSION: Among individuals with prediabetes, several baseline variables were significant predictors of increased SU levels over time. These longitudinal trends in SU, support the potential for early intervention during the prediabetic phase, possibly reducing the risk of gout.

Gender differences in the relationship between serum uric acid and the long-term prognosis in heart failure: a nationwide study.

BACKGROUND: Serum uric acid (SUA) is an important pathogenetic and prognostic factor for heart failure (HF). Gender differences are apparent in HF. Furthermore, gender differences also exist in the association between SUA and prognosis in various cardiovascular diseases. However, the gender difference for SUA in the prediction of long-term prognosis in HF is still ambiguous. METHODS: A total of 1593 HF patients (897 men, 696 women) from the National Health and Nutrition Examination Survey (NHANES) 1999-2018 cycle were enrolled in our final analysis. Participants were categorized according to gender-specific SUA tertile. We assessed the association between SUA and long-term prognosis of HF patients, defined as all-cause mortality and cardiovascular mortality, in different genders via Kaplan-Meier curve analysis, Cox proportional hazard model, and Fine-Gray competing risk model. The restricted cubic spline (RCS) was performed to investigate the dose-response relationship between SUA and outcomes. RESULTS: Gender differences exist in demographic characteristics, clinical parameters, laboratory tests, and medication of HF patients. After a median follow-up of 127 months (95% CI 120-134 months), there were 853 all-cause deaths (493 events in men, 360 events in women) and 361 cardiovascular deaths (206 events in men, 155 events in women). Kaplan-Meier analysis showed that SUA had gender difference in the prediction of cardiovascular mortality (Log-rank p < 0.001, for male, Log-rank p = 0.150, for female), but not in all-cause mortality. Multivariate Cox regression analysis revealed that elevated SUA levels were associated with higher all-cause mortality and cardiovascular mortality in men (HR 1.11, 95% CI 1.05-1.18, p < 0.001, for all-cause death; HR 1.18, 95% CI 1.09-1.28, p < 0.001, for cardiovascular death), but not in women (HR 1.05, 95% CI 0.98-1.12, p = 0.186, for all-cause death; HR 1.01, 95% CI 0.91-1.12, p = 0.902, for cardiovascular death). Even using non-cardiovascular death as a competitive risk, adjusted Fine-Gray model also illustrated that SUA was an independent predictor of cardiovascular death in men (SHR 1.17, 95% CI 1.08-1.27, p < 0.001), but not in women (SHR 0.98, 95% CI 0.87 - 1.10, p = 0.690). CONCLUSIONS: Gender differences in the association between SUA and long-term prognosis of HF existed. SUA was an independent prognostic predictor for long-term outcomes of HF in men, but not in women.

Association of uric acid and fructose levels in polycystic ovary syndrome.

STUDY QUESTION: Is there a relationship between serum uric acid and fructose levels in polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: Elevated serum uric acid levels in women with PCOS positively correlate with serum fructose levels, and elevated serum fructose levels are an independent risk factor for hyperuricemia in women with PCOS. WHAT IS KNOWN ALREADY: Our previous study suggested a link between elevated serum fructose levels and PCOS. Fructose is unique as it generates uric acid during metabolism, and high uric acid levels are associated with metabolic disorders and an increased risk of anovulation. However, the relationship between serum uric acid and fructose levels in women with PCOS remains unclear. STUDY DESIGN, SIZE, DURATION: In a case-control study of 774 women (482 controls and 292 patients with PCOS) between May and October 2020 at the Shengjing Hospital of China Medical University, the relationship between uric acid and fructose levels in women with PCOS was examined. Participants were divided into subgroups based on various factors, including BMI, insulin resistance, dyslipidemia, metabolic syndrome, and hyperuricemia. PARTICIPANTS/MATERIALS, SETTING, METHODS: Serum uric acid concentrations were measured using enzymatic assays, and serum fructose levels were determined using a fluorescent enzyme immunoassay. Dietary fructose data were collected through a validated food-frequency questionnaire of 81 food items. We applied restricted cubic splines to a flexibly model and visualized the linear/nonlinear relationships between serum uric acid and fructose levels in PCOS. Multivariate logistic analysis was executed to assess the association between serum fructose levels and hyperuricemia in PCOS. Human granulosa cell and oocyte mRNA profile sequencing data were downloaded for mapping uric acid and fructose metabolism genes in PCOS. Further downstream analyses, including Gene Ontology, Kyoto Encyclopedia of Genes and Genomes analysis, and protein-protein interactions were then carried out on the differentially expressed genes (DEGs). The correlation between uric acid and fructose metabolism genes was calculated using the Pearson correlation coefficient. The GeneCards database was used to identify DEGs related to uric acid and fructose metabolism in PCOS, and then several DEGs were confirmed by quantitative real-time PCR. MAIN RESULTS AND THE ROLE OF CHANCE: Both serum fructose and uric acid levels were significantly increased in women with PCOS compared with the control women (P < 0.001), and there was no statistically significant difference in dietary fructose intake between PCOS and controls, regardless of metabolic status. There was a positive linear correlation between serum uric acid and fructose levels in women with PCOS (Poverall < 0.001, Pnon-linear = 0.30). In contrast, no correlation was found in control women (Poverall = 0.712, Pnon-linear = 0.43). Additionally, a non-linear association was observed in the obese subgroup of patients with PCOS (Poverall < 0.001, Pnon-linear = 0.02). Serum uric acid levels were linearly and positively associated with serum fructose levels in patients with PCOS with insulin resistance, dyslipidemia, and metabolic syndrome. Furthermore, even after adjusting for confounding factors, elevated serum fructose levels were an independent risk factor for hyperuricemia in patients with PCOS (P = 0.001; OR, 1.380; 95% CI, 1.207-1.577). There were 28 uric acid and 25 fructose metabolism genes which showed a significant correlation in PCOS. Seven upregulated genes (CAT, CRP, CCL2, TNF, MMP9, GCG, and APOB) related to uric acid and fructose metabolism in PCOS ovarian granulosa cells were ultimately successfully validated using quantitative real-time PCR. LIMITATIONS, REASONS FOR CAUTION: Due to limited conditions, more possible covariates (such as smoking and ethnicity) were not included, and the underlying molecular mechanism between fructose and uric acid levels in women with PCOS remains to be further investigated. WIDER IMPLICATIONS OF THE FINDINGS: The results of this study and our previous research indicate that the high uric acid status of PCOS may be mediated by fructose metabolism disorders, highlighting the importance of analyzing fructose metabolism, and especially its metabolic byproduct uric acid, during the clinical diagnosis of PCOS. These results suggest the adverse effects of high uric acid in PCOS, and the importance of taking early interventions regarding uric acid levels to reduce the occurrence and development of further clinical signs, such as metabolic disorders in women with PCOS. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by: the National Natural Science Foundation of China (No. 82371647, No. 82071607, and No. 32100691); LiaoNing Revitalization Talents Program (No. XLYC1907071); Fok Ying Tung Education Foundation (No. 151039); and Outstanding Scientific Fund of Shengjing Hospital (No. 202003). No competing interests were declared. TRIAL REGISTRATION NUMBER: N/A.

Studying the role of Bombyx mori molybdenum cofactor sulfurase in Bombyx mori nucleopolyhedrovirus infection.

Molybdenum cofactor sulfurase (MoCoS) is a key gene involved in the uric acid metabolic pathway that activates xanthine dehydrogenase to synthesise uric acid. Uric acid is harmful to mammals but plays crucial roles in insects, one of which is the immune responses. However, the function of Bombyx mori MoCoS in response to BmNPV remains unclear. In this study, BmMoCoS was found to be relatively highly expressed in embryonic development, gonads and the Malpighian tubules. In addition, the expression levels of BmMoCoS were significantly upregulated in three silkworm strains with different levels of resistance after virus infection, suggesting a close link between them. Furthermore, RNAi and overexpression studies showed that BmMoCoS was involved in resistance to BmNPV infection, and its antivirus effects were found to be related to the regulation of uric acid metabolism, which was uncovered by inosine- and febuxostat-coupled RNAi and overexpression. Finally, the BmMoCoS-mediated uric acid pathway was preliminarily confirmed to be a potential target to protect silkworms from BmNPV infection. Overall, this study provides new evidence for elucidating the molecular mechanism of silkworms in response to BmNPV infection and new strategies for the prevention of viral infections in sericulture.

Dynamic LVEF Decline and Serum NT-proBNP and Uric Acid Levels before Heart Transplantation are Independent Predictors of Adverse Outcomes in Young Adult Patients with Dilated Cardiomyopathy.

Background: The present study investigated the predictors of adverse outcomes in young adult patients with dilated cardiomyopathy (DCM) who underwent heart transplantation (HTx). Methods: Twenty-four young adult patients (aged 18-45 years) with DCM who underwent HTx in our hospital from January 2012 to December 2022 were included in this retrospective analysis. Pre- and post-HTx data were collected for echocardiography, N-terminal pro-brain natriuretic peptide (NT-proBNP), and uric acid (UA). Data collected at the time of DCM diagnosis were designated as baseline data. Post-HTx assessments were conducted at 1 week and 3, 6, 12, and 36 months post-HTx. The primary endpoint was defined as any adverse event, including left ventricular ejection fraction (LVEF) < 50% (n = 3), 50% increase in right or left ventricular diameter (n = 12), or death (n = 2). Patients were categorized into a non-adverse-event group (n = 12) or an adverse-event group (n = 12). Results: Baseline NT-proBNP (p = 0.014) and UA (p = 0.012) were significantly higher in the adverse-event group than in the non-adverse-event group. Baseline NT-proBNP > 7390 pg/mL (relative risk (RR) = 7.412, p = 0.046), UA > 542 µmol/L (RR = 8.838, 95% confidence interval (95% CI) = 1.541-50.694, p = 0.014), and sustained reduction in LVEF ( ≥ 3%) over a 2-year pharmacological treatment prior to HTx (RR = 3.252, p = 0.046) were significantly associated with an increased risk of adverse events post-HTx. Conclusions: In young adult DCM patients post-HTx, heightened baseline levels of NT-proBNP and UA levels and a sustained reduction in LVEF over time prior to undergoing an HTx are significantly associated with an increased risk of adverse events post-HTx. Future studies are needed to observe whether individualized monitoring strategies could reduce the incidence of adverse events following HTx in these patients.