A high level of uric acid is associated with long-term adverse cardiovascular outcomes in patients who received fractional flow reserve with coronary intermediate stenosis.

BACKGROUND AND AIMS: The role of fractional flow reserve (FFR) in coronary intermediate lesions is widely recommended by guidelines. The effect of uric acid (UA) on cardiovascular events is also well known. However, the relationship between UA and long-term cardiovascular outcomes in patients who received FFR with intermediate lesions remains unknown. METHODS AND RESULTS: We retrospectively included 428 patients who underwent both coronary angiography (CAG) and FFR. Participants were stratified into two groups based on the median UA. The primary endpoint was the composite of major adverse cardiovascular and cerebrovascular events (MACCEs), including repeat revascularization, nonfatal stroke, nonfatal myocardial infarction, and all-cause death. A Cox proportional hazards model was utilized to analyze the association between UA and the prevalence of MACCEs. During a median follow-up of 5.8 years, a higher MACCEs rate occurred in the high UA group compared to the low UA group (16.8% vs. 5.1%, p log-rank<0.01). Elevated UA was independently linked to a higher incidence of MACCEs, whether UA was treated as a categorical or continuous variable (hazard ratio [HR] 2.76, 95% confidence interval [CI] 1.27-6.03 or HR 1.01, 95% CI 1.01-1.02). The restricted cubic spline (RCS) analysis illustrated that the HR for MACCEs increased with increasing UA. CONCLUSION: The present study demonstrates that UA is associated with MACCEs risk and suggests that UA is a reliable predictor of long-term cardiovascular events in coronary intermediate stenosis patients.

Hyperuricemia: An Intriguing Connection to Metabolic Syndrome, Diabetes, Kidney Disease, and Hypertension.

PURPOSE OF THE REVIEW: Our review explores the epidemiology, physiology, and clinical data surrounding the connection between hyperuricemia and metabolic syndrome, chronic kidney disease, and hypertension. RECENT FINDINGS: Compelling physiologic mechanisms have been proposed to explain a causal relationship between hyperuricemia and metabolic syndrome, chronic kidney disease, and hypertension but clinical studies have given mixed results in terms of whether intervening with hyperuricemia using urate-lowering therapy has any beneficial effects for patients with these conditions. Despite the large amount of research already put into this topic, more randomized placebo-controlled trials are needed to more firmly establish whether a cause-effect relationship exists and whether lowering uric acid levels in patients with these conditions is beneficial.

Relationship between hyperuricemia with deposition and sexual dysfunction in males and females.

PURPOSE: The association between gout, the most common crystal arthropathy, and sexual dysfunctions has often been investigated by studies in the last decades. Despite the presence of shared risk factors and comorbidities and the possible effects on sexual health of long-term gout complications, awareness of this association is severely lacking and the pathogenetic mechanisms have only partially been identified. In the present review, we aimed to investigate the current evidence regarding the potential mechanisms linking sexual dysfunctions and gout. METHODS: A comprehensive literature search within PubMed was performed to provide a summary of currently available evidence regarding the association between gout and sexual dysfunctions. RESULTS: Gout and sexual dysfunctions share several risk factors, including diabesity, chronic kidney disease, hypertension, metabolic syndrome, and peripheral vascular disease. Gout flares triggered by intense inflammatory responses feature severe pain and disability, resulting in worse sexual function, and some, but not all, treatments can also impair sexual health. Long-term gout complications can result in persistent pain and disability due to joint deformity, fractures, or nerve compression, with negative bearing on sexual function. The presence of low-grade inflammation impairs both sex steroids synthesis and endothelial function, further advancing sexual dysfunctions. The psychological burden of gout is another issue negatively affecting sexual health. CONCLUSIONS: According to currently available evidence, several biological and psychological mechanisms link sexual dysfunctions and gout. Addressing risk factors and providing adequate treatment could potentially have beneficial effects on both conditions. Appropriate clinical evaluation and multidisciplinary approach are recommended to improve patient care.

Topiroxostat versus allopurinol in patients with chronic heart failure complicated by hyperuricemia: A prospective, randomized, open-label, blinded-end-point clinical trial.

BACKGROUND: The benefits of xanthine oxidase inhibitors to chronic heart failure (CHF) patients is controversial. We investigated the beneficial effects of a novel xanthine oxidoreductase inhibitor, topiroxostat, in patients with CHF and hyperuricemia (HU), in comparison to allopurinol. METHODS AND RESULTS: The prospective, randomized open-label, blinded-end-point study was performed in 141 patients with CHF and HU at 4 centers. Patients were randomly assigned to either topiroxostat or allopurinol group to achieve target uric acid level ≤6.0 mg/dL. According to the protocol, 140 patients were followed up for 24 weeks. Percent change in ln (N-terminal-proB-type natriuretic peptide) at week 24 (primary endpoint) was comparable between topiroxostat and allopurinol groups (1.6±8.2 versus -0.4±8.0%; P = 0.17). In the limited number of patients with heart failure with reduced ejection fraction (HFrEF) (left ventricle ejection fraction <45%), ratio of peak early diastolic flow velocity at mitral valve leaflet to early diastolic mitral annular motion velocity (E/e') decreased in topiroxostat group, but not in allopurinol group. Urinary 8-hydroxy-2'-deoxyguanosine and L-type fatty acid-binding protein levels increased and osmolality decreased significantly in allopurinol group, while these changes were less or absent in topiroxostat group. In allopurinol group HFrEF patients, additional to the increases in these urinary marker levels, urinary creatinine levels decreased, with no change in clearance, but not in topiroxostat group. CONCLUSIONS: Compared with allopurinol, topiroxostat did not show great benefits in patients with CHF and HU. However, topiroxostat might have potential advantages of reducing left ventricular end-diastolic pressure, not worsening oxidative stress in proximal renal tubule, and renoprotection over allopurinol in HFrEF patients.

Prognostic value of hyperuricemia for patients with sepsis in the intensive care unit.

This study evaluated the relationship between hyperuricemia at admission and the clinical prognosis of patients with sepsis. The data were obtained from the Intensive Care Medical Information Database III. The patients were divided into a normal serum uric acid group and a hyperuricemia group. The main outcome was 90-day mortality, and the secondary outcomes were hospital mortality, 30-day mortality, and acute kidney injury. Propensity score matching was used to balance the baseline characteristics of the groups. Our study retrospectively included 954 patients. Before and after propensity score matching, the incidence of AKI, the 30-day and 90-day mortality rates were significantly higher in the hyperuricemia group. Cox regression analysis showed that hyperuricemia was significantly associated with 90-day mortality (HR 1.648, 95% CI 1.215-2.234, p = 0.006), and hyperuricemia was significantly associated with the incidence of AKI (HR 1.773, 95% CI 1.107-2.841, p = 0.017). The Kaplan-Meier survival curve showed that the 90-day survival rate was significantly lower in the hyperuricemia group. In patients with sepsis in the intensive care unit, hyperuricemia was significantly associated with increased risk 90-day all-cause mortality and the incidence of AKI.

Erectile dysfunction in hyperuricemia: A prevalence meta-analysis and meta-regression study.

BACKGROUND: Whether and to what extent an association exists between hyperuricemia and erectile dysfunction (ED) has not yet been fully determined. OBJECTIVE: To define pooled prevalence estimates and correlates of erectile dysfunction in men with hyperuricemic disorders. MATERIALS AND METHODS: A thorough search of Medline, Scopus, and Cochrane Library databases was performed. Data were combined using random-effects models and the between-study heterogeneity was assessed by Cochrane's Q and I2 tests. A funnel plot was used to assess publication bias. RESULTS: Overall, 8 studies included gave information about 85,406 hyperuricemic men, of whom 5023 complained of erectile dysfunction, resulting in a pooled erectile dysfunction prevalence estimate of 33% (95% Confidence Interval: 13-52%; I² = 99.9%). The funnel plot suggested the presence of a publication bias. At the meta-regression analyses, among the available covariates that could affect estimates, only type 2 diabetes mellitus was significantly associated with a higher prevalence of erectile dysfunction (ß = 0.08; 95% Confidence Interval: 0.01, 0.15, p = 0.025). At the sub-group analysis, the pooled erectile dysfunction prevalence decreased to 4% (95% Confidence Interval: 0%-8%) when only the largest studies with the lowest prevalence of type 2 diabetes mellitus were included and increased up to 50% (95% Confidence Interval: 17%-84%) when the analysis was restricted to studies enrolling smaller series with higher prevalence of type 2 diabetes mellitus. CONCLUSIONS: A not negligible proportion of men with hyperuricemia can complain of erectile dysfunction. While a pathogenetic contribution of circulating uric acid in endothelial dysfunction cannot be ruled out, the evidence of a stronger association between hyperuricemia and erectile dysfunction in type 2 diabetes mellitus points to hyperuricemia as a marker of systemic dysmetabolic disorders adversely affecting erectile function.

Serum 25-hydroxyvitamin D might be negatively associated with hyperuricemia in U.S. adults: an analysis of the National Health and Nutrition Examination Survey 2007-2014.

PURPOSE: The results of previous studies on the relationship between serum 25-hydroxyvitamin D [25(OH)D] and hyperuricemia are controversial. We hypothesized that serum 25(OH)D concentrations of U.S. adults would negatively correlate with the risk of hyperuricemia. METHOD: Data came from the National Health and Nutrition Examination Survey 2007-2014 were used, after excluding those who met at least one of the exclusion criteria, a total of 9096 male individuals and 9500 female individuals aged 18 years or older were included. Binary logistic regression analysis and restricted cubic spline with fully adjusted confounding factors were applied to evaluate the association between serum 25(OH)D and hyperuricemia. We further performed stratified analysis and sensitivity analysis to minimize the influence of gender, metabolic syndrome, obesity and renal dysfunction on the above association. RESULTS: We found a negative correlation between serum 25(OH)D and hyperuricemia. In the binary logistic regression analysis, compared with the highest serum 25(OH)D quartile [Q4: 25(OH)D > 77.10 nmol/L] group, the odds ratios (95% confidence intervals) in the lowest quartile [Q1: 25(OH)D ≤ 43.20 nmol/L] was 1.46 (1.22-1.75) in the fully adjusted model. Restricted cubic spline analysis showed L-shaped and non-linear relationships between 25(OH)D and hyperuricemia. In sensitivity analysis, after restricting to participants without significant renal dysfunction and obesity, the above association remained significant. After restricting to participants who were diagnosed as metabolic syndrome, above association remained significant in the fully adjusted model. In stratified analysis by gender, the association remained significant among males and females. CONCLUSIONS: Serum 25(OH)D might be inversely associated with hyperuricemia in general U.S. adults. From our study, for people with unexplained hyperuricemia, screening for serum Vitamin D concentration might be necessary.

Natural Xanthine Oxidase Inhibitor 5-O-Caffeoylshikimic Acid Ameliorates Kidney Injury Caused by Hyperuricemia in Mice.

Xanthine oxidase (XOD) inhibition has long been considered an effective anti-hyperuricemia strategy. To identify effective natural XOD inhibitors with little side effects, we performed a XOD inhibitory assay-coupled isolation of compounds from Smilacis Glabrae Rhizoma (SGR), a traditional Chinese medicine frequently prescribed as anti-hyperuricemia agent for centuries. Through the in vitro XOD inhibitory assay, we obtained a novel XOD inhibitor, 5-O-caffeoylshikimic acid (#1, 5OCSA) with IC50 of 13.96 µM, as well as two known XOD inhibitors, quercetin (#3) and astilbin (#6). Meanwhile, we performed in silico molecular docking and found 5OCSA could interact with the active sites of XOD (PDB ID: 3NVY) with a binding energy of -8.6 kcal/mol, suggesting 5OCSA inhibits XOD by binding with its active site. To evaluate the in vivo effects on XOD, we generated a hyperuricemia mice model by intraperitoneal injection of potassium oxonate (300 mg/kg) and oral gavage of hypoxanthine (500 mg/kg) for 7 days. 5OCSA could inhibit both hepatic and serum XOD in vivo, together with an improvement of histological and multiple serological parameters in kidney injury and HUA. Collectively, our results suggested that 5OCSA may be developed into a safe and effective XOD inhibitor based on in vitro, in silico and in vivo evidence.

The Prognostic Value of Serum Uric Acid in Hospitalized Patients with Acute Cerebral Infarction.

BACKGROUND: Previous studies reported that the level of serum uric acid (SUA) was an important risk factor for acute cerebral infarction (ACI). However, the prognostic value of SUA levels in hospitalized patients with ACI has not been fully elucidated. The aim of this study was to investigate whether the SUA level on admission was associated with subsequent mortality in hospitalized patients with ACI. METHODS: The clinical data of ACI patients obtained from December 2017 to December 2019 were retrospectively reviewed. χ 2 and Kaplan-Meier methods were used to compare the clinical differences and overall survival between patients with or without hyperuricemia, respectively. Univariate and multivariate analyses were used to identify independent prognoses. RESULTS: In the total population, the in-hospital mortality of the hyperuricemia group was significantly higher than that of the normal uric acid group (P = 0.006). In the abnormal renal function group, the in-hospital mortality among the hyperuricemia group was significantly higher than the normal uric acid group (P = 0.002). However, there was no statistical difference of in-hospital mortality between the two groups in the normal renal function group (P = 0.321). Univariate and multivariate analyses showed that a previous history of diabetes (P = 0.018), hyperuricemia (P = 0.001), and National Institutes of Health Stroke Scale (NIHSS) score on admission (P ≤ 0.001) were independent factors for all samples. The hyperuricemia (P = 0.003) on admission were independent factors for patients with abnormal renal function. CONCLUSIONS: In ACI patients with abnormal renal function, hyperuricemia may be associated with higher in-hospital mortality than patients with normal uric acid, and hyperuricemia may be an independent associated factor for in-hospital death in the subgroup patients.

Eggshell Membrane Ameliorates Hyperuricemia by Increasing Urate Excretion in Potassium Oxonate-Injected Rats.

Hyperuricemia is the primary cause of gouty arthritis and other metabolic disorders. Eggshell membrane (EM) is an effective and safe supplement for curing pain and stiffness connected with osteoarthritis. However, the effect of EM on hyperuricemia is unclear. This study determines the effects of EM on potassium oxonate-injected hyperuricemia. Uric acid, creatinine, blood urea nitrogen concentrations in the serum, and xanthine oxidase activity in the liver are measured. Protein levels of renal urate transporter 1 (URAT1), organic anion transporters 1 (OAT1), glucose transporter 9 (GLUT9), and ATP-binding cassette transporter G2 (ABCG2) in the kidney are determined with renal histopathology. The results demonstrate that EM reduces serum uric acid levels and increases urine uric acid levels in hyperuricemic rats. Moreover, EM downregulates renal URAT1 protein expression, upregulates OAT1 and ABCG2, but does not change GLUT9 expression. Additionally, EM does not change xanthine oxidase activity in the liver or the serum. EM also decreases uric acid uptake into oocytes expressing hURAT1. Finally, EM markedly reduces renal inflammation and serum interleukin-1ß levels. These findings suggest that EM exhibits antihyperuricemic effects by promoting renal urate excretion and regulating renal urate transporters. Therefore, EM may be useful in the prevention and treatment of gout and hyperuricemia.

The effects of hyperuricemia on endothelial cells are mediated via GLUT9 and the JAK2/STAT3 pathway.

BACKGROUND: Uric acid (UA) transporters mediate the uptake and outflow of UA, and are greatly involved in the control of UA concentrations. Glucose transporter 9 (GLUT9), one of the UA transporters, has been confirmed to be expressed in human umbilical vein endothelial cells (HUVECs). This study aimed to characterize GLUT9's effect on intracellular UA accumulation in HUVECs in a high-UA environment and to explore the mechanism of cellular dysfunction. METHODS AND RESULTS: HUVECs were treated with UA to establish a model of cellular dysfunction. Then, UA uptake, GLUT9 expression and endothelial nitric oxide synthase (eNOS) and reactive oxygen species (ROS) amounts were measured. UA uptake was concentration- and time-dependent, and UA treatment significantly reduced nitric oxide (NO) levels and eNOS activity. UA also upregulated pro-inflammatory molecules and GLUT9, and increased intracellular ROS amounts in HUVECs. GLUT9 knockdown reduced UA uptake and ROS content, but antioxidant treatment did not reduce GLUT9 expression. To assess the function of JAK2/STAT3 signaling, HUVECs were treated with UA, and the phosphorylation levels of JAK2, STAT3, IL-6 and SOCS3 were increased by a high concentration of UA. In addition, GLUT9 knockdown reduced the phosphorylation of JAK2/STAT3 intermediates and increased p-eNOS amounts. CONCLUSIONS: GLUT9 mediated the effects of high UA levels on HUVECs by increasing the cellular uptake of UA, activating JAK2/STAT3 signaling, and reduced the production of active eNOS and NO in HUVECs.

Multiparametric MRI analysis for the evaluation of renal function in patients with hyperuricemia: a preliminary study.

BACKGROUND: To investigate the renal dysfunction in patients with hyperuricemia by employing a multiparametric MRI protocol, consisting of quantitative water molecule diffusion, microstructure, microscopic perfusion, and oxygenation measurements in kidneys. MATERIALS AND METHODS: A total of 48 patients with hyperuricemia (HU) and 22 age-matched healthy control subjects (HC) were enrolled in the study. For each participant, three different functional magnetic resonance imaging (fMRI) sequences were acquired and analyzed, including intravoxel incoherent motion imaging (IVIM), diffusion tensor imaging (DTI), and blood-oxygen-level-dependent MRI (BOLD). Thereafter, an independent two-sample t-test was applied to discover the significant differences of MRI indices between the hyperuricemia (HU) and HC groups, and the specific potential biomarkers between two subgroups of HU group (asymptomatic hyperuricemia group (AH) and gouty arthritis group (GA)). Further, multivariate logistic regression analyses were performed to classify the AH from the GA group using the MRI indices with significant between-group differences. The receiver operating characteristic (ROC) curve was plotted, and the area under the ROC curve (AUC) was calculated to assess the performance of each MR index for differentiation between the AH and GA groups. RESULTS: Ten parametric values of the HU group were significantly lower than those of the HC group among the 14 fMRI parameters (P < 0.05). The cortical D, D*, and f values and medullary D and R2*values had significant differences between the AH and GA groups (P < 0.05). Combining the cortical D and f values and medullary R2* value gave the best diagnostic efficacy, yielding an AUC, sensitivity, and specificity of 0.967 ± 0.022, 91.67%, and 95.83%, respectively. CONCLUSIONS: A multiparametric MR analysis plays an important role in the evaluation of renal dysfunction in hyperuricemia from multiple perspectives. It could be a promising method for noninvasive detection and identification of the early-stage renal damage induced by hyperuricemia.

Hepatic and Renal Impacts of Lesinurad on Experimental Hyperuricemia: Biochemical, Molecular and Pathological Investigations.

<b>Background and Objective:</b> Hyperuricemia is one of the most dangerous threats to human life. It is mainly associated with gout and inflammatory arthritis. Therefore, finding a safe medication that does not have severe side-effects is a goal shared by most physicians. The current study aimed to evaluate the effect of lesinurad (Zurampic; ZUR) and allopurinol (ALP), both alone or in combination, on the treatment of hyperuricemic mice at the biochemical, molecular and cellular levels. <b>Materials and Methods:</b> Lesinurad and allopurinol were orally administered to hyperuricemic and control mice for seven consecutive days, either alone or in combination. Levels of uric acid and xanthine oxidase activity, blood urea nitrogen, creatinine, ALT and AST were measured in the serum. The mRNA expression of mouse hepatic guanine deaminase (Gda), purine nucleotide phosphorylase (PNP), renal urate anion transporter-1 (URAT-1) and OAT-1 transporters were examined. The renal tissues were examined using H and E staining and the immunoreactivity technique. <b>Results:</b> Lesinurad and allopurinol administration resulted in a significant decrease in serum levels of uric acid, blood urea nitrogen and xanthine oxidase activity reported in hyperuricemic mice. Both partially reversed oxonate-induced alterations in renal mURAT-1 and mOAT-1 expressions, as well as alterations in the immunoreactivity of Bcl2. All showed an increase in renal uric acid secretion and excretion. ALP and ZUT significantly decreased the increase in Gda and PNP expression reported in hyperuricemic mice. The combined administration of ZUR and ALP restored and improved renal function histopathological changes reported in hyperuricemic mice. <b>Conclusion:</b> The hypouricemic impact of both lesinurad and allopurinol in the treatment of hyperuricemia in mice was confirmed following hyperuricemia treatment.

Comparative study of a novel selective urate reabsorption inhibitor "dotinurad" among patient groups with different stages of renal dysfunction.

BACKGROUND: Dotinurad is a selective urate reabsorption inhibitor (SURI), which selectively inhibits URAT1 to lower serum uric acid levels in patients with hyperuricemia. Herein, the effects of dotinurad were compared among patient groups with different stages of renal dysfunction. METHODS: Patient data from four clinical trials were pooled and divided into four groups according to the stage of renal dysfunction to compare the effects of dotinurad at different stages. The grouping (stages G1-G3b) was based on the estimated glomerular filtration rate (eGFR) of the patients. In addition, patient data from a long-term study (34 or 58 weeks) were evaluated in the same manner. RESULTS: In the pooled analysis, the percentage of patients achieving a serum uric acid level of ≤ 6.0 mg/dL was 64.7-100.0% at a dose of 2 or 4 mg. In the long-term analysis, the percentage of patients achieving a serum uric acid level of ≤ 6.0 mg/dL was 60.0-100.0% at a dose of 2 or 4 mg. Although the outcomes in stage G3b were worse due to higher baseline serum uric acid levels, satisfactory outcomes were observed in all stages. Even in stages G3a and G3b, when renal function declined, the eGFR remained constant throughout the dose period. CONCLUSION: The efficacy of dotinurad was confirmed in hyperuricemic patients with normal renal function (stage G1) and mild to moderate renal dysfunction (stage G2-G3b). Dotinurad was found to be effective in the treatment of hyperuricemia in patients with mild to moderate renal dysfunction.

Uric acid as a cardiorenal mediator: pathogenesis and mechanistic insights.

Introduction: The role of serum uric acid as a connector in cardiorenal interactions has been long debated and studied extensively in the past decade. Epidemiological, and clinical data suggest that hyperuricemia may be an independent risk factor as well as a strong predictor of morbidity and mortality in cardiovascular diseases (CVD) and renal diseases. New data suggesting that urate lowering therapies may improve outcomes in cardiovascular diseases have generated interest.Areas Covered: This review attempts to summarize the pathophysiological mechanisms by which hyperuricemia causes cardiorenal dysfunction. It also provides a summary of the recent evidence for urate lowering therapies and the possible underlying mechanisms which lead to cardiovascular benefits. This was a narrative review with essential references or cross references obtained via expert opinion.Expert Opinion: Emphasis on newer drugs that address the cardio-renal metabolic axis and the relation to their effects on uric acid may help further elucidate underlying mechanisms responsible for their cardiovascular and renal benefits. Once these benefits are well established, we will be able to come up with guidelines for targeting hyperuricemia. This can potentially lead to a change in clinical practice and can possibly lead to improved cardiovascular and renal outcomes.

The Impact of hyperuricemia on long-term clinical outcomes of renal transplant recipients: a systematic review and meta-analysis.

PURPOSE: To evaluate the effect of hyperuricemia on clinical outcomes of renal transplant recipients (RTRs). METHODS: A literature search of PubMed, Cochrane, Embase was conducted up to March 20, 2020. The primary outcome was the estimated glomerular filtration rate (eGFR). The second outcomes were the risk of graft loss, death, cardiovascular event and the level of triglyceride. The following search terms were utilized: ((Hyperuricemic group) OR (Hyperuricaemia) OR (Hyperuric) OR (Urea acid) OR (Uric acid) OR (Acid urate) OR (Urate) OR (Gout)) and ((Transplantation) OR (Transplantations) OR (Transplant) OR (Transplants) OR (Graft)). RESULTS: 28 studies with 18224 patients were eligible for inclusion. There was no significant difference in eGFR (<12 months, p=0.07), the risk of graft loss (<60 months, p=0.07) and death (<60months, p=0.19) between the hyperuricemic and normouricemic group in the early post-transplantation period. But increased uric acid levels contributed to the long-term decline of eGFR, the risk of graft loss and death increased after transplantation. Hyperuricemia increased the risk of cardiovascular event with no significant difference in the level of triglyceride between the two groups. CONCLUSIONS: Increased uric acid levels contributed to the long-term decline of eGFR, increased risk of graft loss and death after transplantation. Although there was no significant effect on triglyceride, hyperuricemia increased the risk of cardiovascular event.

T1rho mapping of cartilage and menisci in patients with hyperuricaemia at 3 T: a preliminary study.

AIM: To compare and assess T1rho values of the femorotibial cartilage compartments and subregional menisci in patients with hyperuricaemia at 3 T. MATERIALS AND METHODS: Thirty-two patients were enrolled in the study and were subdivided into two subgroups: 15 healthy controls (three women, 12 men; mean age = 45.3 ± 10.9 years, age range 25-72 years) and 17 patients with asymptomatic hyperuricaemia (two women, 15 men; mean age = 44.4 ± 12.7 years, age range 26-77 years). All patients were evaluated using 3 T magnetic resonance imaging (MRI) using an eight-channel phased-array knee coil (transmit-receive). Wilcoxon's rank sum test and analysis of covariance (ANCOVA) were conducted to determine whether there were any statistically significant differences in the T1rho values of the femorotibial cartilage compartments and subregional menisci between the two subgroups. RESULTS: Lateral tibial cartilage (45.8 ± 2.9 ms) in the healthy subgroup had significantly lower (p<0.05) T1rho values than those of all subcompartments of the femorotibial cartilage in the hyperuricaemia subgroup. The lateral femoral cartilage (LF) in hyperuricaemia (54.6 ± 3.9 ms) subgroup had significantly higher (p<0.05) T1rho values than those of all subcompartments of the femorotibial cartilage except the LF in the healthy subgroup. Significantly higher (p<0.05) T1rho values existed in the LF of the healthy (54.6 ± 4.7 ms) subgroup in comparison with those of all subcompartments of femorotibial cartilage except the LF in hyperuricaemia subgroup. CONCLUSIONS: T1rho values in certain compartments of the femorotibial cartilage in patients with hyperuricaemia are elevated compared to those in healthy patients presumably due to reduced proteoglycan content, to which particular attention should be paid when diagnosing and treating the patients with hyperuricaemia in a clinical setting.

Apigenin ameliorates hyperuricemic nephropathy by inhibiting URAT1 and GLUT9 and relieving renal fibrosis via the Wnt/ß-catenin pathway.

BACKGROUND: Hyperuricemia (HUA) is characterized by abnormal serum uric acid (UA) levels and demonstrated to be involved in renal injury leading to hyperuricemic nephropathy (HN). Apigenin (API), a flavonoid naturally present in tea, berries, fruits, and vegetables, exhibits various biological functions, such as antioxidant and anti-inflammatory activity. PURPOSE: To investigate the effect of API treatment in HN and to reveal its underlying mechanisms. METHODS: The mice with HN were induced by potassium oxonate intraperitoneally and orally administered for two weeks. The effects of API on renal function, inflammation, fibrosis, and uric acid (UA) metabolism in mice with HN were evaluated. The effects of API on urate transporters were further examined in vitro. RESULTS: The mice with HN exhibited abnormal renal urate excretion and renal dysfunction accompanied by increased renal inflammation and fibrosis. In contrast, API reduced the levels of serum UA, serum creatinine (CRE), blood urea nitrogen (BUN) and renal inflammatory factors in mice with HN. Besides, API ameliorated the renal fibrosis via Wnt/ß-catenin pathway suppression. Furthermore, API potently promoted urinary UA excretion and inhibited renal urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) in mice with HN. In vitro, API competitively inhibited URAT1 and GLUT9 in a dose-dependent manner, with IC50 values of 0.64 ± 0.14 µM and 2.63 ± 0.69 µM, respectively. CONCLUSIONS: API could effectively attenuate HN through co-inhibiting UA reabsorption and Wnt/ß-catenin pathway, and thus it might be a potential therapy to HN.

Gout-induced endothelial impairment: The role of SREBP2 transactivation of YAP.

Gout is a multifaceted inflammatory disease involving vascular impairments induced by hyperuricemia. Experiments using human umbilical vein endothelial cells treated with uric acid (UA), monosodium urate (MSU), or serum from gout patients showed increased expression of pro-inflammatory genes (ie, VCAM1, ICAM1, CYR61, CCNA1, and E2F1) with attendant increase in monocyte adhesion. Mechanistically, UA- or MSU-induced SREBP2 expression and its transcriptional activity. RNA sequencing analysis and real-time PCR showed the induction of YAP signaling and pro-inflammatory pathways in HUVECs transfected with adenovirus-SREBP2. The SREBP2 knockdown by siRNA partially abolished UA- or MSU-induced YAP activity, pro-inflammatory gene expression, and monocytes adhesion. Vascular intima from transgenic mice overexpressing SREBP2 in endothelium or mice with hyperuricemia exhibited activated YAP signaling and increased expression of pro-inflammatory genes. Betulin, an SREBP pharmacological inhibitor, attenuated the UA-, MSU-, or gout serum-induced endothelial cell inflammation and dysfunction. In the human study, endothelial cell function, assessed by EndoPAT, was negatively correlated with serum UA level among gouty patients and healthy controls. Collectively, UA or MSU causes endothelial dysfunction via SREBP2 transactivation of YAP. Betulin inhibition of SREBP2 may restrain gout-induced endothelial dysfunction.