Associations of polycyclic aromatic hydrocarbons exposure with serum uric acid and hyperuricemia in US adults: The role of systemic inflammation.

The associations of polycyclic aromatic hydrocarbon (PAH) exposure with serum uric acid (SUA) or hyperuricemia have been rarely assessed. We aimed to investigate the relationships between urinary PAH metabolites and SUA or hyperuricemia among US adults and to explore the mediating role of systemic inflammation in the associations. A total of 10,307 US adults were conducted to assess the associations of seven urinary hydroxy­PAH with SUA and hyperuricemia and evaluate the role of C-reactive protein (CRP), a biomarker of systemic inflammation, in such associations. Results showed that each 1-unit increase in ln-transformed 2-hydroxynaphthalene (2-OHNa), 1-hydroxyphenanthrene (1-OHPh), 2&3-hydroxyphenanthrene (2&3-OHPh) and total hydroxyphenanthrene (ΣOHPh) was associated with a 1.68 (95% confidence interval (CI): 0.19 to 3.17), 2.46 (0.78 to 4.13), 3.34 (1.59 to 5.09), and 2.99 (1.23 to 4.75) µmol/L increase in SUA, and a 8% (odds ratio (OR): 1.08, 1.02 to 1.15), 9% (OR: 1.09, 1.02 to 1.18), 13% (OR: 1.13, 1.05 to 1.22), and 12% (OR: 1.12, 95% CI: 1.03, 1.21) increase in hyperuricemia, respectively. Co-exposure of seven PAHs was positively associated with SUA and hyperuricemia, with 2&3-OHPh showing the highest weight (components weights: 0.83 and 0.78, respectively). The CRP mediated 11.47% and 10.44% of the associations of ΣOHPh and 2&3-OHPh with SUA and mediated 8.60% and 8.62% in associations of ΣOHPh and 2&3-OHPh with hyperuricemia, respectively. In conclusion, internal levels of PAH metabolites were associated with elevated SUA levels and the increased risk of hyperuricemia among US adults, and CRP played a mediating role in the associations.

Ilex cornuta leaves extracts ameliorate hyperuricemia by modulating uric acid transporters.

ETHNOPHARMACOLOGICAL RELEVANCE: Ilex cornuta is a valuable species of the Holly genus (Aquifoliaceae), and mainly distributed in eastern China. It is not only made into tea, namely Kudingcha, but also used as traditional medicine to relieve cough, headache, gout, and nourish liver and kidney. AIM OF THE STUDY: The purpose of this study was to explore the exact efficacy of different extracts from Ilex cornuta in the treatment of hyperuricemia in vitro and in vivo, and to explore its pharmacological mechanism, so as to bring new ideas for the development of new drugs for reducing uric acid (UA) and anti-gout. MATERIALS AND METHODS: Five crude extracts from Ilex cornuta leaves were extracted by different methods. Then, the xanthine oxidase inhibitory activity and antioxidant capacity of 5 extracts in vitro were compared to screen the extract with the most UA regulating potential. In vivo experiment, hyperuricemia model of mice was established by intragastric administration of potassium oxonate and feeding high yeast diet. Biochemical indexes such as serum UA level, xanthine oxidase activity, liver and kidney index of mice in each group were detected. The pathological sections of kidney and liver tissues were also observed and compared. The mechanism of Ilex cornuta leaves (western blotting, and RT-qPCR) in the treatment of hyperuricemia was further explored by targeting UA transporters ABCG2, GLUT9, and URAT1. RESULTS: The in vitro results of inhibitory activity of xanthine oxidase showed that the crude saponin extract was the best, followed by crude flavonoids extract. Then, the in vivo results reflected that both crude saponins and crude flavonoids extracts could significantly reduce the serum UA level, inhibit the activity of xanthine oxidase in serum and liver, and maintain serum urea nitrogen and creatinine at normal level. Meanwhile, there was no liver and kidney injury in mice. Through the comparison of the mechanism results, it was found that both extracts could up-regulate the expression of ABCG2 protein and mRNA related to UA excretion, and down-regulate the expression of GLUT9 and URAT1 protein and mRNA. CONCLUSION: The crude flavonoids and saponins of Ilex cornuta leaves not only inhibited XOD activity in vitro, but also significantly controlled XOD activity and reduced UA level in hyperuricemia mice in vivo. One of the potential mechanisms was to regulate UA level in vivo by regulating ABCG2, GLUT9, and URAT1 transporters directly related to UA transport, thus achieving the effect of intervening hyperuricemia. This study provided a preliminary experimental basis for the development of new drugs of Ilex cornuta leaves for treating hyperuricemia.

Serum uric acid: an independent risk factor for cardiovascular disease in Pakistani Punjabi patients.

BACKGROUND: It is well-known that serum uric acid (SUA) can increase the risk of hypertension, diabetes, obesity and dyslipidemia. However, its independent association with the risk of cardiovascular diseases (CVD) is controversial particularly in different populations. Hence, this study was aimed to assess an independent association of SUA with CVD risk in a Punjabi Pakistani cohort. METHODS: This is a retrospective observational study in which 502 human subjects having CVD, hypertension and/or diabetes were grouped based on SUA levels as normouricemia (n = 266) and hyperuricemia (n = 236). Role of SUA was assessed in increasing the risk of CVD independent of other key confounding factors (i.e. age, gender, dyslipidemia, hypertension, diabetes, dietary and life-style habits). All clinical and biochemical data were analyzed in SPSS (ver. 20). RESULTS: Subjects aged 55 ± 13 years were of both genders (males: 52%). SUA levels were significantly different among clinical subtypes of CVD [i.e. acute coronary syndrome (ACS), myocardial infarction (MI) and heart failure (HF)]. Spearman correlation showed a significantly positive association between CVD and SUA (rho = 0.149, p < 0.001). Multivariate logistic regression of SUA quartiles showed that hyperuricemia is associated with CVD [3rd quartile: OR: 1.78 (CI: 1.28-2.48), p = 0.001 and 4th quartile: OR: 2.37 (CI: 1.72-3.27), p < 0.001]. Moreover, this association remained significant even after adjusting for confounding factors. CONCLUSION: This study showed that SUA is positively associated with CVD, thus it can act as an independent risk factor for CVD.

From Patents to Progress: Unraveling Gout's Journey Through Clinical Trials and Advancements.

Gout, an inflammatory arthritis form, is renowned for its historical association with affluence. This review delves into its pathophysiology, exploring hyperuricemia, urate crystal formation, and the ensuing inflammatory response. The epidemiology of gout is examined, focusing on its rising prevalence and impact on public health. In this study, progress in gout management is discussed, involving pharmacological interventions, dietary changes, and emerging therapies. Genetic predisposition and triggers like alcohol, temperature, and diet are highlighted in this study. Prevention strategies, including serum urate-lowering therapy and lifestyle modifications, aim to reduce recurrent flares and complications. The inflammatory response in acute gout attacks is elucidated, involving immune cells, cytokines, and the NLRP3 inflammasome. Chronic gout manifestations, such as gouty tophus formation, are explored for their destructive impact on surrounding tissues. Recent advancements in gout treatment, including nanotherapies and novel compounds, are discussed, along with promising urate-lowering drugs. Cutting-edge research on zinc ferrite nanoparticles, dimethyl fumarate, and myricetin/nobiletin hybrids addresses oxidative stress and inflammation in gout. Additionally, the potential therapeutic role of methanolic leaf extract of Euphorbia milii and tip-loaded CLC-Soluplus® MAPs is explored as natural and transdermal alternatives for gout management. The review also covers the development status of new urate-lowering drugs, providing insights into promising candidates and their mechanisms. Patents on gout and recent diagnostic advancements using techniques like laser confocal micro Raman spectrometer, FTIR, and THz-TDS offer a more accurate approach for gout stone analysis, enabling early detection and targeted treatment.

Knowledge, attitude, and practice toward hyperuricemia among healthcare workers in Shandong, China.

Background: Hyperuricemia is a relatively common condition, with a prevalence of over 20% among the general population. Also, most patients initially present no symptoms. This study aimed to investigate the knowledge, attitude, and practice (KAP) toward hyperuricemia among healthcare workers in Shandong, China. Methods: Healthcare workers were recruited in this cross-sectional study conducted in Shandong in December 2022. A self-designed questionnaire was used to collect demographic information and KAP data. Results: A total of 372 questionnaires were distributed, and 216 (58.06%) valid questionnaires were collected from 131 physicians, 80 nurses, and five other healthcare workers. The participants had a mean score of 10.76 ± 2.53 (possible range: 0-14, 76.9%) and 31.94 ± 2.58 (possible range: 0-40, 79.9%) in knowledge and attitude, respectively. The physicians' and nurses' practice scores were 47.57 ± 5.34 (possible range: 0-55, 86.5%) and 30.06 ± 4.11 (possible range: 0-35, 85.9%), respectively. The attitude scores were independently associated with proactive practice in both physicians (P < 0.001) and nurses (P = 0.046). Conclusion: This study found that healthcare workers in Shandong had adequate knowledge, positive attitudes, and proactive practices towards hyperuricemia. However, there is room for improvement in the attitudes of both physicians and nurses to achieve better practice.

Effect of konjac glucomannan on gut microbiota from hyperuricemia subjects in vitro: fermentation characteristics and inhibitory xanthine oxidase activity.

Background: The disorder of uric acid metabolism is closely associated with gut microbiota and short-chain fatty acids (SCFAs) dysregulation, but the biological mechanism is unclear, limiting the development of uric acid-lowering active polysaccharides. Konjac glucomannan (KGM) could attenuate metabolic disturbance of uric acid and modulate the gut microbiota. However, the relationship between uric acid metabolism and gut microbiota is still unknown. Methods: In this study, The fecal samples were provided by healthy volunteers and hyperuricemia (HUA) patients. Fecal samples from healthy volunteers was regarded as the NOR group. Similarly, 10% HUA fecal suspension was named as the HUA group. Then, fecal supernatant was inoculated into a growth basal medium containing glucose or KGM, and healthy fecal samples were designated as the NOR-GLU and NOR-KGM groups, while HUA fecal samples were designated as the HUA-GLU and HUA-KGM groups. All samples were cultured in an anaerobic bag system. After fermentation for 24 h, the samples were collected for further analysis of composition of intestinal microbiota, SCFAs concentration and XOD enzyme activity. Results: The results showed that KGM could be utilized and degraded by the gut microbiota from HUA subjects, and it could modulate the composition and structure of their HUA gut microbiota to more closely resemble that of a healthy group. In addition, KGM showed a superior modulated effect on HUA gut microbiota by increasing Megasphaera, Faecalibacterium, Lachnoclostridium, Lachnospiraceae, Anaerostipes, and Ruminococcus levels and decreasing Butyricicoccus, Eisenbergiella, and Enterococcus levels. Furthermore, the fermentation solution of KGM showed an inhibitory effect on xanthine oxidase (XOD) enzyme activity, which might be due to metabolites such as SCFAs. Conclusion: In conclusion, the effect of KGM on hyperuricemia subjects was investigated based on the gut microbiota in vitro. In the present study. It was found that KGM could be metabolized into SCFAs by HUA gut microbiota. Furthermore, KGM could modulate the structure of HUA gut microbiota. At the genus level, KGM could decrease the relative abundances of Butyricicoccus, Eisenbergiella, and Enterococcus, while Lachnoclostridium and Lachnospiraceae in HUA gut microbiota were significantly increased by the addition of KGM. The metabolites of gut microbiota, such as SCFAs, might be responsible for the inhibition of XOD activity. Thus, KGM exhibited a superior probiotic function on the HUA gut microbiota, which is expected as a promising candidate for remodeling the HUA gut microbiota.

Downregulation of type I interferon signalling pathway by urate in primary human PBMCs.

Type I interferons (IFN1s) mediate innate responses to microbial stimuli and regulate interleukin (IL)-1 and IL-1 receptor antagonist (Ra) production in human cells. This study explores interferon-stimulated gene (ISG) alterations in the transcriptome of patients with gout and stimulated human primary cells in vitro in relation to serum urate concentrations. Peripheral blood mononuclear cells (PBMCs) and monocytes of patients with gout were primed in vitro with soluble urate, followed by lipopolysaccharide (LPS) stimulation. Separately, PBMCs were stimulated with various toll-like receptor (TLR) ligands. RNA sequencing and IL-1Ra cytokine measurement were performed. STAT1 phosphorylation was assessed in urate-treated monocytes. Cytokine responses to IFN-ß were evaluated in PBMCs cultured with or without urate and restimulated with LPS and monosodium urate (MSU) crystals. Transcriptomics revealed suppressed IFN-related signalling pathways in urate-exposed PBMCs or monocytes which was supported by diminishment of phosphorylated STAT1. The stimulation of PBMCs with IFN-ß did not modify the urate-induced inflammation. Interestingly, in vivo, serum urate concentrations were inversely correlated to in vitro ISG expression upon stimulations with TLR ligands. These findings support a deficient IFN1 signalling in the presence of elevated serum urate concentrations, which could translate to increased susceptibility to infections.

Effect of the Xanthine Oxidase Inhibitor Febuxostat on the Cardio-Ankle Vascular Index in Asymptomatic Patients with Hyperuricemia and Liver Dysfunction: A Sub-Analysis of the PRIZE Study.

AIMS: The effect of uric acid (UA)-lowering therapy with xanthine oxidoreductase (XOR) inhibitors on the development of cardiovascular disease requires further investigation. This study aimed to evaluate the long-term effects of febuxostat on arterial stiffness, focusing on liver function. METHODS: The PRIZE study involved random assignment of patients with asymptomatic hyperuricemia to receive either add-on febuxostat treatment (febuxostat group) or non-pharmacological treatment (control group). Of the 514 participants, 23 and 14 patients in the febuxostat and control groups, respectively, underwent assessment of arterial stiffness using the cardio-ankle vascular index (CAVI). The participants in each group were further grouped on the basis of their baseline alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels (above or below the media value or 30 U/L). The primary endpoint was the change in the CAVI from baseline to 12 and 24 months. RESULTS: Overall, no significant differences were found between the control and febuxostat groups in the least-squares mean estimates of changes in CAVI at 24 months (mean between-group difference, -0.41 [95% CI, -1.05 to 0.23]; p=0.204). However, there were significant differences in participants with higher baseline ALT or AST levels above 30 U/L at 24 months (mean between-group difference, -1.12 [95% CI, -2.23 to -0.01]; p=0.048 for ALT ≥ 30 U/L and -1.08 [95% CI, -2.13 to -0.03]; p=0.044 for AST ≥ 30 U/L). CONCLUSIONS: Two-year treatment with febuxostat demonstrated a beneficial effect on CAVI in patients with hyperuricemia and liver dysfunction.

Associations of Dietary Magnesium Intake with All-Cause and Cause-Specific Mortality Among Individuals with Gout and Hyperuricemia.

We aimed to evaluate the relationship of dietary magnesium intake with all-cause and cause-specific mortality among patients with gout and hyperuricemia (HUA). We analyzed data of 1171 gout patients and 6707 HUA patients from the National Health and Nutrition Examination Survey (NHANES) 2007-2018 and 2001-2018, respectively. Dietary intake data were obtained from 24-h dietary recall interviews. Mortality status was determined using the NHANES public-use linked mortality fill. We used Cox regression model and restricted cubic spline analysis to probe the association of dietary magnesium intake and mortality among gout and HUA patients. During 7081 person-years of follow-up, 257 deaths were documented in gout patients, among which 74 died from cardiovascular disease (CVD) and 48 died from cancer. For HUA patients followed up for 58,216 person-years, 1315 all-cause deaths occurred, including 411 CVD deaths and 224 cancer deaths. After multifactorial adjustments, higher dietary magnesium intake was associated with lower risk of all-cause mortality. Nonlinear negative associations were found between dietary magnesium intake and CVD mortality among gout and HUA patients, with inflection points of 152.5 mg/day and 303 mg/day, respectively, and cancer mortality among HUA patients, with the inflection point of 232 mg/day. The results were robust in subgroup and sensitivity analyses. High dietary magnesium intake is linearly related to all-cause mortality, and nonlinearly associated with cause-specific mortality among gout and HUA patients.

Energy insufficiency induced by high purine diet: Catalysts for renal impairment in hyperuricemia nephropathy rat model.

A high purine diet emerges as a significant risk factor for hyperuricemia, and this diet may potentiate hyperuricemia nephropathy. Despite this, the mechanistic underpinnings of kidney damage precipitated by a high purine diet warrant further research. In the current investigation, a hyperuricemia nephropathy rat model was developed through induction via a high purine diet. Subsequently, metabolomic and proteomic analyses were employed to explore the metabolic characteristics of the kidney and shed light on the corresponding mechanistic pathway. Finally, fluorescence imaging and 18F-fluorodeoxyglucose positron emission tomography computed tomography (18F-FDG-PET/CT) were utilized to validate the overarching energy metabolism state. The results revealed extensive damage to the kidneys of hyperuricemia nephropathy rats following eight weeks of induction via a high purine diet. We used metabolomic to found that acyl carnitines and L-carnitine reduced in high purine diet group, indicated abnormal fatty acid metabolism. Irregularities were discerned in metabolites and enzymes associated with fatty acid ß-oxidation, glycolysis, and oxidative phosphorylation within the kidneys of hyperuricemia nephropathy rats by proteomic and co-expression network analysis. The application of fluorescence imaging and 18F-FDG-PET/CT substantiated the inhibition of fatty acid ß-oxidation and glycolysis within the kidneys of hyperuricemia nephropathy rats. On the contrary, a compensatory enhancement in the function of oxidative phosphorylation was observed. Given that the primary energy supply for renal function was derived from the metabolic pathway of fatty acids ß-oxidation, any disruption within this pathway could contribute to a deficit in the energy provision to the kidneys. Such an energy insufficiency potentially laid the groundwork for eventual renal impairment. In addition, inhibition of the peroxisome proliferator-activated receptors signaling pathway was noted in the present findings, which could further exacerbate the impediment in the ß-oxidation function. In conclusion, it was discerned that a deficiency in energy supply plays a critical role in the kidney injury in hyperuricemia nephropathy rats, thereby endorsing paying more attention to renal energy supply in the therapy of hyperuricemia nephropathy.

Systemic Inflammation In Asymptomatic Hyperuricemia With Sonographic Crystal Deposits, Including A Comparison With Normouricemia And Gout.

OBJECTIVE: To describe the inflammatory profile of asymptomatic hyperuricemia (AH) with ultrasound evidence of monosodium urate (MSU) crystals (AH-MSUpos), vs AH without deposits (AH-MSUneg), intercritical gout, and normouricemia. METHODS: Based on serum urate levels, musculoskeletal ultrasound, and history of flares, we divided 122 participants into four groups: normouricemia, AH-MSUneg, AH-MSUpos, and intercritical gout. We tested four ultrasound definitions for MSU deposition in AH: grade 2-3 (G2-3) double contour and/or tophi, G1-3 double contour and/or tophi, G1-3 Stewart scheme (double contour sign in knee cartilage and/or first metatarsophalangeal joint and/or tophi in first metatarsophalangeal joint), and G2-3 Stewart scheme. Serum acute phase reactants, cytokines, pyroptosis derivates, and neutrophil-related proteins were measured and compared between groups. A linear regression model was fitted to correlate crystal and inflammatory burden (measured by ultrasound) with inflammatory markers in hyperuricemics. RESULTS: Rates of MSU deposition in AH ranged from 26.0% to 68.8%, depending on the definition used. Levels of CRP, leukocytes, IL-1RA, IL-6, sIL-6R, IL-18, TNF-α, TGF-ß, and galectin-3 were higher in hyperuricemics vs normouricemics. Sex, obesity, and comorbidity scores influenced some comparisons. We saw no differences comparing AH-MSUpos  vs AH-MSUneg groups, except for higher calprotectin using G1-3 sonographic definitions and higher CRP and TGF-ß when restricted to women and obese participants. CONCLUSIONS: Hyperuricemia is associated with substantial inflammation and some degree of active pyroptosis. Four different ultrasound definitions for AH with MSU deposits yielded similar findings, although we noted some differences in calprotectin, CRP, and TGF-ß. Sex, obesity, and comorbidities influenced some inflammatory responses.

The Association of Dietary Diversity with Hyperuricemia among Community Inhabitants in Shanghai, China: A Prospective Research.

Hyperuricemia, a major worldwide burden on public hygiene, is closely connected with dietary habits. However, few studies have evaluated the association of dietary diversity with hyperuricemia. To preliminarily reveal the status of a diversified diet in preventing hyperuricemia based on a neighborhood-based, massive-scale cohort in China, a total of 43,493 participants aged 20-74 years old, with no history of hyperuricemia at baseline, were enrolled in the research from April 2016 to December 2019. The Dietary Diversity Score (DDS) was utilized to evaluate the dietary variety and split the participants into the low-, medium-, and high-DDS groups. Information on participants was connected to regional health information systems that acquired data on hyperuricemia instances up to 28 February 2023. Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed by Cox proportional hazards models. Restricted cubic splines (RCS) were implemented to analyze dose-response correlation. A total of 1460 individuals with newly diagnosed hyperuricemia were observed over a median follow-up period of 5.59 years. Compared to the low-DDS group, HRs for the medium- and high-DDS groups were 0.87 (95% CI 0.76-0.99) and 0.80 (95% CI 0.70-0.91) in the fully adjusted model, respectively. The risk of hyperuricemia incidence was reduced by 5% for each 1 unit of DDS increase. A linear correlation of DDS with hyperuricemia emerged and further revealed that the intake of 8-10 broad categories of food could decrease the incidence of hyperuricemia. Our results validate the dietary principle of "food diversification" recommended in guidelines. Conclusions should be applied with caution considering the paucity of related evidence in additional nations.

Hyperuricemia and associated factors among hypertensive patients attending an academic hospital of Ethiopia: A cross-sectional study.

Background: Hypertension is a major public health problem in developing countries. Globally, nearly 1.13 billion adults had hypertension in 2015 and this is estimated to increase to 1.56 billion by 2025. Hyperuricemia is an important predictor of the progression of hypertension and is common in hypertensive patients. Hypertensive patients with hyperuricemia are at higher risk of cardiovascular disease. Objective: To assess the prevalence of hyperuricemia and its associated factors among hypertensive patients attending the University of Gondar Comprehensive Specialized Hospital (UGCSH). Method: An institutional-based cross-sectional study was conducted on 248 hypertensive patients attending the University of Gondar Comprehensive Specialized Hospital from January 2020 to February 2021. A convenient sampling technique was employed to select study participants. Socio-demographic and clinical characteristics were collected using a structured questionnaire via face-to-face interviews and reviewing medical records respectively. The biochemical parameters were measured by using a Mindray BS-200E chemistry analyzer. Data was entered using EpiData version 4.6.0.0 and analyzed using STATA vs. 14.0. Bivariable and multivariable binary logistic regression were fitted to identify factors associated with hyperuricemia. The odds ratio and 95 % CI were calculated to assess the strength of the association and a P-value <0.05 in the multivariable was considered statistically significant. Results: A total of 248 patients were enrolled; 140 (56.5 %) were female. The mean age of patients was 57.9 ± 10.5 years. The overall prevalence of hyperuricemia was 42.3 %; males had a prevalence of 36.1 % and females of 47.1 %. High waist circumference, high body mass index, dyslipidemia, low estimated Glomerular Filtration Rate, elevated fasting blood glucose, elevated total cholesterol, elevated triglycerides, elevated Low-Density Lipoprotein cholesterol, and Low High-Density Lipoprotein cholesterol were found to be significantly associated with hyperuricemia. Conclusion: This study demonstrated the predominant existence of hyperuricemia in hypertensive patients. Therefore, early diagnosis and monitoring of hyperuricemia are required before further complications occur.

Gout or Hyperuricemia and Dementia Risk: A Meta-Analysis of Observational Studies.

Background: As a natural antioxidant, uric acid has neuroprotective effects. The association between uric acid levels and dementia risk was reported by previous studies. However, recently published studies showed that the relationship between uric acid and dementia risk might be heterogeneous in dementia subtypes. Objective: This study aimed to clarify the relationship between hyperuricemia (or gout) and dementia. Methods: The PubMed and Web of Science databases were systematically searched up to April 2024 to identify relevant studies. A meta-analysis was conducted using hazard ratios (HR) or odds ratios (OR) and 95% confidence interval (CI) as pooled indicators. Heterogeneity between the studies was examined using Cochran's Q statistic and I2 statistic. Subgroup analyses were conducted for gender and age. Stratification analysis, sensitivity analyses and meta-regression were conducted to explore possible explanations for heterogeneity. Publication bias was assessed by funnel plot and Egger's test. Results: A total of 11 studies met the inclusion criteria including 2,928,152 participants were abstracted. Hyperuricemia (or gout) did not reduce the overall risk of dementia (OR/HR = 0.92, 95% CI: 0.81-1.05) and vascular dementia (OR/HR = 0.74, 95% CI: 0.53-1.05), but may have a protective effect against Alzheimer's disease (OR/HR = 0.82, 95% CI: 0.70-0.96). Subgroup analysis showed that a lower risk of dementia was observed in men (OR/HR = 0.83, 95% CI: 0.77-0.90) and patients whose age under 65 (OR/HR = 0.83, 95% CI: 0.72-0.95). Conclusions: Patients with gout or hyperuricemia have a low risk of Alzheimer's disease.

Hyperuricemia Facilitates Uric Acid-Mediated Vascular Endothelial Cell Damage by Inhibiting Mitophagy.

Hyperuricemia remains an elusive factor in the pathogenesis of vascular endothelial injury. This study elucidates the role of hydroxychloroquine (HCQ) in the context of uric acid (UA)-induced vascular endothelial cell damage. Human umbilical vein endothelial cells (HUVECs) were exposed to varying UA concentrations (6 mg/dL to 50 mg/dL) for 48 h, or to 50 mg/dL UA for different time points (6 to 72 h). We observed a concentration- and time-dependent inhibition of cell proliferation, particularly at 40 mg/dL and 50 mg/dL UA. The autophagy marker LC3 exhibited reduced fluorescence intensity post-UA treatment, along with decreased expression of LC3-II/LC3I, beclin1, and p62, indicating impaired autophagy. The mechanistic exploration revealed that HCQ, in conjunction with the mitochondrial autophagy inhibitor Cyclosporine A (CsA), exacerbated the inhibitory effects of UA on HUVEC autophagy. This was evidenced by a further reduction in mitochondrial autophagy-related proteins and diminished fluorescence of LC3-II/LC3-I and Parkin, culminating in suppressed cell proliferation and accelerated cell senescence and apoptosis. Conversely, the co-treatment with the mitochondrial autophagy inducer carbonyl cyanide m-chlorophenyl hydrazine (CCCP) and HCQ mitigated the detrimental effects of UA on HUVEC autophagy. This intervention led to increased expression of PINK1, Parkin, Bnip3, and Nix, along with enhanced fluorescence of LC3-II/LC3-I and Parkin, effectively inhibiting cell senescence and apoptosis while promoting cell proliferation. In conclusion, our findings underscore the pivotal role of HCQ in modulating UA-mediated vascular endothelial cell damage through the inhibition of mitophagy, providing novel insights into the therapeutic potential of targeting HCQ in the management of hyperuricemia-associated vascular complications.

Febuxostat leads to better cardiovascular outcomes compared to allopurinol in patients with advanced chronic kidney disease: A Population-based Cohort Study.

OBJECTIVE: Hyperuricemia is a risk factor for cardiovascular disease complications in patients with chronic kidney disease. The impact of febuxostat on cardiovascular disease in advanced chronic kidney disease remains unclear. This study aimed to explore the cardiovascular benefits of xanthine oxidase inhibitors, particularly febuxostat and allopurinol, in patients with advanced chronic kidney disease. METHODS: A retrospective population-based cohort study was conducted using data from Taiwan's National Health Insurance Research Database (NHIRD) (2006-2017). The TriNetX dataset served as an external validation dataset. The study involved 13,187 patients with advanced chronic kidney disease treated with febuxostat or allopurinol. After propensity score matching, a balanced cohort of 976 patients (488 in each arm) was created. Hazard ratios (HRs) were calculated for all-cause mortality and hospitalizations, utilizing the competing risk regression model. RESULTS: Febuxostat was associated with lower all-cause mortality (HR, 0.79; 95% confidence interval [CI], 0.64-0.98) and fewer hospitalizations (HR, 0.53; 95% CI, 0.44-0.63) than allopurinol. After adjustments, febuxostat also reduced hospitalizations for heart failure (HR, 0.59; 95% CI, 0.43-0.80) and infection (HR, 0.65; 95% CI, 0.52-0.82). This cardiovascular benefit of febuxostat was consistently observed in the TriNetX dataset. Moreover, subgroup analysis revealed that febuxostat was better in reducing death and heart failure events than allopurinol across most of the subgroups. CONCLUSIONS: Febuxostat may confer cardioprotective effects in patients with advanced chronic kidney disease compared with allopurinol, thereby potentially useful in reducing cardiovascular risks in this high-risk population.

Design, synthesis, and evaluation of chalcone derivatives as xanthine oxidase inhibitors.

Xanthine oxidase (XO) is an important enzyme that catalyzes the oxidation of hypoxanthine to xanthine and xanthine to uric acid in the catabolism of purines in humans. This makes XO a well-recognized target in alleviating hyperuricemia. The present study adapted a structure-based drug discovery approach to develop potent and low-toxicity XO inhibitors with the chalcone skeleton. We introduced a carboxyl group and a hydroxyl group to the B ring and modified the A ring. 35 chalcone derivatives were designed and synthesized. All the 35 derivatives exhibited higher XO inhibition activities (IC50 = 0.064-0.559 µM) compared with allopurinol (IC50 = 2.588 µM). Their high affinity was attributed to strong hydrogen bond interactions formed between the introduced carboxyl and hydroxyl groups with key amino acid residues in XO. SAR analysis disclosed that carboxyl, hydroxyl, ethyl (12c), methylamino (12h), dimethylamino (12i), indolin (13k), and indol (13l) groups played important roles in improving the whole molecules' inhibition potency against XO. ADME predictions and cytotoxicity assays suggested their pharmacokinetic characteristics and biocompatibility were desirable. Additionally, 12c exhibited a significant hypouricemic effect on potassium oxonate-induced hyperuricemia rats after orally administrated at a dose range of 10-40 mg/kg, representing a promising anti-hyperuricemia potential for further optimization and development.

Serum creatinine is more strongly associated with hyperuricemia than eGFR in males but not in females.

OBJECTIVES: Serum creatinine and estimated glomerular filtration ratio (eGFR) are factors associated with hyperuricemia, though which is more closely associated with hyperuricemia remains unclear. SUBJECTS AND METHODS: This retrospective cross-sectional study examined the associations of serum creatinine and eGFR with hyperuricemia using health check-up findings. Enrolled were 6020 individuals (3509 males, 2511 females) who underwent health check-ups from 2017 to 2021. The subjects were divided based on serum uric acid level into the normuricemia (males 1.5-7.0 mg/dl, females 1.5-< 6.0 mg/dl) and hyperuricemia (males >7.0 mg/dl, female ≥ 6.0 mg/dl) groups. Matched-pair analysis was used to evaluate the association between hyperuricemia and variables related to serum uric acid. RESULTS: Matched-pair analysis results showed a significant association of serum creatinine with hyperuricemia in male subjects but not in females. Furthermore, propensity score obtained by binominal logistic regression demonstrated that serum creatinine had a greater association with hyperuricemia than eGFR in the males but not in females. CONCLUSIONS: The present findings indicate an association of serum creatinine with hyperuricemia in males not only because of reduced renal function but other factors related to greater muscle mass, such as increased intake of protein-rich foods containing purines and increased uric acid production induced by accelerated creatinine metabolism.

Association between Visceral Adiposity Index and Hyperuricemia among Steelworkers: The Moderating Effects of Drinking Tea.

BACKGROUND/OBJECTIVES: Steelworkers are more likely to have a higher prevalence of hyperuricemia due to their exposure to special occupational factors and dietary habits. The interrelationships of visceral adiposity index (VAI), hyperuricemia, and drinking tea remain uncertain. This study aimed to assess the association between VAI and hyperuricemia among steelworkers, and if drinking tea modified this association. METHODS: A total of 9928 steelworkers from Hunan Hualing Xiangtan Iron and Steel Company participated in this cross-sectional study. All participants completed a questionnaire, received anthropometric measurements, and provided blood samples for biochemical testing. Three logistic regression models were used to analyze the association between VAI and hyperuricemia. RESULTS: In this study, the prevalence of hyperuricemia was approximately 23.74% (males: 24.41%; females: 20.63%), and a positive correlation between VAI and hyperuricemia risk was observed. In multivariate logistic regression analysis, the risk of hyperuricemia increased 1.76 times (95% CI: 1.64-1.89) and 2.13 times (95% CI: 1.76-2.57) with the increase of ln VAI in males and females, respectively. For males, compared to quartile 1, the risk of hyperuricemia in the second, third, and fourth quartile of VAI were 1.75 (95% CI: 1.11-2.71), 2.56 (95% CI: 1.67-3.93) and 4.89 (95% CI: 3.22-7.43). For females, compared to quartile 1, the risk of hyperuricemia in the second, third, and fourth quartile of VAI were 1.99 (95% CI: 1.40-2.82), 2.92 (95% CI: 1.96-4.34) and 4.51 (95% CI: 2.89-7.02). Additionally, our study found that, compared with not consuming tea, drinking tea could reduce uric acid levels by 0.014 in male steelworkers (t = -2.051, p = 0.040), 0.020 in workers consuming smoked food (t = -2.569, p = 0.010), and 0.022 in workers consuming pickled food (t = -2.764, p = 0.006). CONCLUSIONS: In conclusion, VAI is positively correlated with hyperuricemia in steelworkers. Drinking tea may lower uric acid levels in male steelworkers and steelworkers who prefer smoked and pickled foods.

Life's essential 8 and cardiovascular disease among patients with hyperuricemia: The Kailuan Cohort Study.

OBJECTIVES: Studies have found that a high Life's Essential 8 (LE8) score is associated with a reduced risk of cardiovascular disease(CVD) in cancer populations and young adults. However, the association between LE8 and the risk of CVD in hyperuricemia (HUA) is not fully understood. METHODS: The main analysis included 6814 HUA participants. In a secondary analysis, 5,418 participants were selected from the main analysis to model the trajectory of uric acid (UA) levels from 2006 to 2010. Cox regression model was used to investigate the relationship between LE8 total score and cardiovascular disease risk in different populations. RESULTS: Follow-up of 15.79 years in the main analysis, 986 CVD events occurred. With tertile 1 as the control group, the HR and 95 % CI of CVD in tertile 2 and tertile 3 were 0.75(0.65,0.87) and 0.56(0.47,0.66). In the secondary analysis, the HR and 95 %CI of individuals with low and medium levels of UA reduced CVD were 0.49(0.26,0.89) and 0.56(0.41,0.76), respectively, but this association was not found in individuals with sustained high UA levels. The risk of CVD was different between the sexes. There are differences in cardiovascular disease risk among different age groups. CONCLUSIONS: The risk of CVD in HUA population decreased with the increase of LE8 score, especially in young and middle-aged people and women. However, it is important to note that LE8 may not reduce the risk of CVD in individuals with sustained high UA levels.