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Background and Aims: The objective of this research was to explore the associations between dietary PUFAs intake and hyperuricemia risk., Methods and Results: Based on the National Health and Nutrition Examination Survey (NHANES) 2003-2015, all eligible individuals were divided into hyperuricemia and non-hyperuricemia groups based on diagnostic criteria for hyperuricemia (serum uric acid >420 μmol/L for men and >360 μmol/L for women). Multivariate-adjusted logistic regression was employed to explore the relationship between dietary PUFAs intake and hyperuricemia risk. Total PUFAs and their subtypes were modeled to isocalorically replace saturated fatty acids (SFAs) and monounsaturated fatty acids (MUFAs). Higher intake of n-3 PUFAs, n-6 PUFAs, linoleic acid (LA), alpha-linoleic acid (ALA), and non-marine PUFAs intake correlated with decreased hyperuricemia risk, with adjusted odds ratio (OR) and 95% confidence interval (95%CIs) were 0.77 (0.63, 0.93), 0.75 (0.61, 0.92), 0.75 (0.61, 0.91), 0.69 (0.55, 0.87), and 0.73 (0.59, 0.91), respectively. Replacing 5% of total energy intake from SFAs with isocaloric PUFAs was associated with decreased odds of hyperuricemia in men (0.69 (0.57, 0.84)) and in individuals (0.81 (0.71, 0.92)). Similar trends were observed in the substitution of SFAs with non-marine PUFAs in men (0.87 (0.80, 0.94)) and in all individuals (0.92 (0.88, 0.98)). Sensitivity analyses exhibited consistent results with primary analyses., Conclusion: Higher dietary intake of n-3 PUFAs, n-6 PUFAs, LA, ALA, and non-marine PUFAs was associated with decreased hyperuricemia risk. These results support the recommendation to substitute SFAs with PUFAs in diet., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background and Aim: Currently, the relationship between dynamic changes in dietary manganese (Mn) intake and risk of hyperuricemia (HU) is still unclear. This study aimed to identify dietary Mn consumption trajectories in the Chinese adults and assess their relation with the risk of HU., Methods and Results: Cohort data from the China Health and Nutrition Survey (CHNS) 1997-2009 were employed in this study. Overall, 6886 adult participants were included. Participants were designated into subgroups based on the trajectories of dietary Mn consumption by sex. Cox proportional hazard models were used to explore the associations between different trajectories and the risk of HU. For men, compared with low stable trajectory group, moderate to high trajectory group was significantly related to reduced risk of HU (HR = 0.61, 95% CI: 0.38 to 0.98) with adjustment for covariates. TC, HDL-C, ApoB, and TG exerted partial regulation function between trajectories and HU. For women, compared with low stable trajectory group, high stable trajectory group was significantly related to reduced risk of HU (HR = 0.76, 95% CI: 0.60 to 0.95) with adjustment for covariates. Similarly, TC, HDL-C, ApoB, and ApoA exerted partial regulation function between trajectories and HU., Conclusions: Long-term relatively high dietary Mn consumption may have a protective effect against HU in Chinese adults. The differences in HU-related factors among different dietary Mn intake trajectories partially regulated the association between these trajectories and HU., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Objective: To investigate the nephroprotective potential of orally administered bracken Pteridium aquilinum extract against renal damage in quails, induced by a high-purine diet, to form a foundation for subsequent clinical studies and applications., Materials and Methods: A mass spectrometry analysis was conducted on the pteridophyte subjected to steam explosion. Network pharmacological methods were then utilized to pinpoint shared targets and pathways, which suggested that Pteridium aquilinum has a capability to counteract renal injury. A total of 48 specific-pathogen-free (SPF) "Difaku" quails were selected and segregated into six distinct groups. The control group received a standard diet, whereas the other groups were fed a high-purine diet. Beginning on day 14, each group was subjected to designated therapeutic measures. The study continued for 40 days, after which relevant biological markers were assessed., Results: Active compound peaks from the steam-exploded Pteridium aquilinum were isolated. Subsequently, 101 targets and several pathways associated with renoprotective effects were discerned, indicating that the Pteridium aquilinum achieves its nephroprotective function through comprehensive regulatory mechanisms. The high-purine diet successfully induced hyperuricemia in the quails, resulting in renal impairment. Following intervention with varied Pteridium aquilinum dosages, renal protective outcomes were evident, though xanthine oxidase activity remained unaffected. Histological analyses demonstrated a notable decrease in renal lesion dimensions post-intervention., Conclusion: The steam-exploded bracken Pteridium aquilinum may provide nephroprotective benefits against hyperuricemia-induced renal damage in quails through comprehensive regulatory processes. This highlights the Pteridium aquilinum's potential as an innovative nephroprotective therapeutic and dietary solution, presenting a promising avenue for hyperuricemia and renal damage treatment and prevention.

This study aimed to describe the prevalence of comorbid hypertension and hyperuricemia (HH) and detected the dietary factors for HH in Chinese adults aged 18 to 64 years. All of the data were collected from the China Nutrition and Health Surveillance 2015-2017, with a stratified, multistage, random sampling method on a national scale. A total of 52,627 adult participants aged 18~64 years from the CNHS 2015-2017 were included in this study. HH was identified as SUA level cut-offs for males and females of 420 μmol/L and 360 μmol/L, respectively, with mean systolic blood pressure ≥140 mmHg and/or mean diastolic blood pressure ≥ 90 mmHg and/or received antihypertensive treatment within two weeks. The differences in HH prevalence between or among the subgroups were compared by the Rao-Scott chi-square test. The correlations between HH and covariates or metabolic factors were detected by a weighted two-level multivariate survey logistic regression. The total weighted sufficient intake ratios of beans and nuts, vegetables, and red meat were 59.1%, 46.6%, and 64.8%, respectively. The weighted prevalence of HH in the total participants was 4.7% (95% CI: 4.3-5.0%). The positive effects of bean and nut on HH were observed. The participants who had sufficient bean and nut intake showed lower risk for HH (for the total participants: OR = 0.734, 95% CI = 0.611-0.881). The prevalence of HH might have been a public health problem, and bean and nut intake might be a protective factor for HH in the Chinese population.

Hyperuricemia (HUA) is a prevalent chronic disease, characterized by excessive blood uric acid levels, that poses a significant health risk. In this study, the preventive effects and potential mechanisms of ethanol extracts from Chinese sumac ( Rhus chinensis Mill.) fruits on HUA and uric acid nephropathy were comprehensively investigated. The results demonstrated a significant reduction in uric acid levels in hyperuricemia mice after treatment with Chinese sumac fruit extract, especially in the high-dose group, where the blood uric acid level decreased by 39.56%. Visual diagrams of the kidneys and hematoxylin and eosin (H&E)-stained sections showed the extract's effectiveness in protecting against kidney damage caused by excessive uric acid. Further investigation into its mechanism revealed that the extract prevents and treats hyperuricemia by decreasing uric acid production, enhancing uric acid excretion, and mitigating the oxidative stress and inflammatory reactions induced by excessive uric acid in the kidneys. Specifically, the extract markedly decreased xanthine oxidase (XOD) levels and expression in the liver, elevated the expression of uric acid transporters ABCG2, and lowered the expression of uric acid reabsorption proteins URAT1 and SLC2A9. Simultaneously, it significantly elevated the levels of endogenous antioxidant enzymes (SOD and GSH) while reducing the level of malondialdehyde (MDA). Furthermore, the expression of uric-acid-related proteins NLRP3, ACS, and Caspase-3 and the levels of IL-1β and IL-6 were significantly reduced. The experimental results confirm that Chinese sumac fruit extract can improve HUA and uric acid nephropathy in mice fed a high-purine yeast diet. This finding establishes a theoretical foundation for developing Chinese sumac fruit as a functional food or medicine for preventing and treating HUA.

Hyperuricemia represents a great burden on global public health, and it is important to provide effective guidance at the level of dietary patterns. We evaluated the association between the Dietary Approaches to Stop Hypertension (DASH) diet and the risk of hyperuricemia in a large-scale, community-based cohort in East China. In total, 45,853 participants that did not have either hyperuricemia nor gout were included and assigned a DASH dietary score based on their baseline dietary intake. They were then divided into five quintiles (Q1−Q5) according to their score, followed by cross-linkages with local health information systems and in-person surveys. Cox proportional hazards models were adopted to calculate hazard ratio (HR) and 95% confidence intervals (CIs). During a median follow-up of 4.54 years, 2079 newly diagnosed hyperuricemia cases were documented. Compared to the DASH Q1 group, the risk of incident hyperuricemia for the Q5 group was significantly reduced by 16% (HR: 0.84; 95% CIs: 0.72−0.97) in the adjusted model. The associations of DASH diet with hyperuricemia appeared stronger (P for interaction <0.001) among participants with 3−4 cardiometabolic diseases at baseline, compared with their counterparts. Our results suggest that the DASH diet could be taken into account in the recognition of risk population and the prevention of hyperuricemia., Competing Interests: The authors declare no conflicts of interest.

Hyperuricemia (HC) is one of the important risk factors for gout, arteriosclerosis, and cardiovascular disease. Animal studies have shown that Lactobacillus plantarum can improve microbiota and immune regulation, as well as inhibit uric acid production. However, it is not clear whether L. plantarum can improve HC and intestinal microbiota. We used potassium oxonate (PO) to induce HC in male SD rats and then treated them with L. plantarum TCI227 in a dose-dependent manner (HC + LD, HC + MD, HC + HD) for 4 weeks. We examined organ weight, conducted biochemical examinations of blood and urine, and analyzed the intestinal microbiota in feces through a 16s rDNA sequence analysis. In this study, TCI227 improved body weight, decreased creatinine and serum uric acid, and increased urine uric acid compared to the HC group. Furthermore, TCI227 increased short-chain fatty acids (SCFAs). In the fecal microbiota (family), TCI227 increased the level of Lactobacillaceae and then decreased the levels of Deferribacteres and Prevotellaceae compared to the HC group. Finally, in the fecal microbiota (genus), TCI227 decreased the level of Prevotella and then increased the levels of Lactobacillus and Ruminococcus compared to the HC group. This study suggested that TCI227 can improve HC and can change the composition of intestinal microbiota in PO-induced male HC SD rats.

Our current study aimed to estimate the relationship between dietary patterns and hyperuricemia among the Chinese elderly over 60 years old. All the data were obtained from China Nutrition and Health Surveillance during 2015-2017. A total of 18,691 participants who completed the whole survey were included in our statistical analysis. The definition of hyperuricemia was 420 μmmol/L (7 mg/dL) for male and 360 μmmol/L (6 mg/dL) for female. Exploratory factor analysis was applied to explore posterior dietary patterns in our samples, and five dietary patterns were recognized, namely "Typical Chinese", "Modern Chinese", "Western", "Animal products and alcohol", and "Tuber and fermented vegetables". After multiple adjusted logistic regression, participants in the highest quartile of "typical Chinese" (Q4 vs. Q1, OR = 0.32, 95% CI: 0.28-0.37, p -trend < 0.0001), "modern Chinese" (Q4 vs. Q1, OR = 0.81, 95% CI: 0.71-0.93, p -trend = 0.0021) and "tuber and fermented vegetables" (Q4 vs. Q1, OR = 0.78, 95% CI: 0.69-0.88, p -trend < 0.0001) showed a lower risk of hyperuricemia, while animal products and alcohol was positively associated with hyperuricemia (Q4 vs. Q1, OR = 1.49, 95% CI: 1.31-1.7, p -trend < 0.0001). We also found that participants who mainly ate a modern Chinese diet tended to meet the RNI/AI of nutrients we discuss in this paper, which may supply some information for hyperuricemia prevention and management by dietary methods.

Alcohol is recognized a risk factor for increased uric acid and gout flare. The aim of the study was to review the literature in order to find out what is the role of alcohol consumption in pathogenesis of gout. A search in PubMed, Google Scholar, Medline Complete database was performed in January 2021. The databases were searched with the phrases: "uric acid and alcohol," "alcoholic beverages and gout," "hyperuricemia and alcoholic beverages consumption" published between 2000 and 2021. A total of 2642 results were found. The 99 non-duplicate citations were screened. Then 81 articles were excluded after abstract screen. After that 18 articles were retrieved. Eventually 15 articles were included for systematic review. Several authors see the positive correlation between beer or distilled spirits consumption and gout. Some include wine to the list of triggers of gout. Others state that moderate wine consumption protects from gout attacks due to antioxidants and phytoestrogen content. Majority noticed the relationship between episodic alcohol consumption and gout attacks. Episodic alcohol intake triggers gout attacks, regardless of type of alcohol. Thus, individuals with established gout and pre-existing risk factors should limit all types of alcohol intake to prevent gout episodes.

Currently, the most widely used screening methods for hyperuricemia (HUA) involves invasive laboratory tests, which are lacking in many rural hospitals in China. This study explored the use of non-invasive physical examinations to construct a simple prediction model for HUA, in order to reduce the economic burden and invasive operations such as blood sampling, and provide some help for the health management of people in poor areas with backward medical resources. Data of 9252 adults from April to June 2017 in the Affiliated Hospital of Guilin Medical College were collected and divided randomly into a training set (n = 6364) and a validation set (n = 2888) at a ratio of 7:3. In the training set, non-invasive physical examination indicators of age, gender, body mass index (BMI) and prevalence of hypertension were included for logistic regression analysis, and a nomogram model was established. The classification and regression tree (CART) algorithm of the decision tree model was used to build a classification tree model. Receiver operating characteristic (ROC) curve, calibration curve and decision curve analyses (DCA) were used to test the distinction, accuracy and clinical applicability of the two models. The results showed age, gender, BMI and prevalence of hypertension were all related to the occurrence of HUA. The area under the ROC curve (AUC) of the nomogram model was 0.806 and 0.791 in training set and validation set, respectively. The AUC of the classification tree model was 0.802 and 0.794 in the two sets, respectively, but were not statistically different. The calibration curves and DCAs of the two models performed well on accuracy and clinical practicality, which suggested these models may be suitable to predict HUA for rural setting., (© 2021. The Author(s).)

Background: Hyperuricemia induces nephropathy through the mediation of oxidative stress, tubular injury, inflammation, and fibrosis. The high uric acid level is associated with the reduction of vitamin D levels. However, the reno-protective effects of this vitamin in hyperuricemia condition remain unknown. This study aimed to elucidate calcitriol treatment in a uric acid-induced hyperuricemia mice model., Methods: : Uric acid (125 mg/kg body weight [BW]) was administered intraperitoneally for 7 (UA7) and 14 (UA14) days. Calcitriol (0.5 g/kg BW) was intraperitoneally injected for the following seven days, after 14 days of uric acid induction (UA14VD7 group). The control group received NaCl 0.9%, by the same route. Serum creatinine was measured using calorimetric method, and uric acid levels were assessed using enzymatic calorimetric assay. Tubular injury and fibrosis were assessed using PAS and Sirius red staining. RT-PCR and real-time reverse transcription PCR were carried out for the analyses of SOD-1, Collagen-1, and TGF-1 mRNA expression in the kidney. Immunostaining of super oxide dismutase type 1 (SOD-1) was performed to detect its expression in the kidney., Results: Uric acid and creatinine levels markedly increased in UA14 groups, followed by an exacerbation of tubular injury. RT-PCR revealed the upregulation of Collagen-1 and TGF-1, along with the downregulation of SOD-1. Calcitriol treatment attenuated the injury with reducing uric acid and creatinine levels, as well as tubular injury. This was associated with lower Collagen-1 and TGF-1 mRNA expression compared to the UA7 and UA14 groups. SOD-1 was upregulated in epithelial cells in the UA14VD7 group., Conclusion: Calcitriol treatment after uric acid induction may attenuate kidney injury through upregulation of SOD-1 and downregulation of Collagen-1 and TGF-1 gene expression.

Defective permeability barrier is considered to be an incentive of hyperuricemia, however, the link between them has not been proven. Here, we evaluated the potential preventive effects of Lactiplantibacillus plantarum N-1 (LPN1) on gut microbiota and intestinal barrier function in rats with hyperoxaluria-induced kidney stones. Male rats were supplied with 1% ethylene glycol (EG) dissolved in drinking water for 4 weeks to develop hyperoxaluria, and some of them were administered with LPN1 for 4 weeks before EG treatment as a preventive intervention. We found that EG not only resulted hyperoxaluria and kidney stone formation, but also promoted the intestinal inflammation, elevated intestinal permeability, and gut microbiota disorders. Supplementation of LPN1 inhibited the renal crystalline deposits through reducing urinary oxalic acid and renal osteopontin and CD44 expression and improved EG-induced intestinal inflammation and barrier function by decreasing the serum LPS and TLR4/NF-κB signaling and up-regulating tight junction Claudin-2 in the colon, as well as increasing the production of short-chain fatty acid (SCFAs) and the abundance of beneficial SCFAs-producing bacteria, mainly from the families of Lachnospiraceae and Ruminococcaceae. Probiotic LPN1 could prevent EG-induced hyperoxaluria by regulating gut microbiota and enhancing intestinal barrier function., (© 2021 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Objective: Although several individual nutrients/foods are associated with uric acid status, the association of overall diet quality with hyperuricemia remains unclear. The current study was undertaken to examine the association between adherence to the Dietary Approaches to Stop Hypertension (DASH) diet and the odds of having hyperuricemia in a Chinese adult population., Methods: Included were 71,893 Chinese participants in the Kailuan I study and the Kailuan II study (mean age 51.4 years) who were free of gout prior to or in 2014. Dietary intakes were assessed using a validated food frequency questionnaire, and the DASH diet score was calculated based on consumptions of vegetables, fruit, dairy, beans, whole grains, meat, fat, sodium, and sugar-sweetened beverages. Fasting blood samples were collected in 2014, and hyperuricemia was defined as serum uric acid concentrations of ≥7 mg/dl for men, and of ≥6 mg/dl for women. The association between DASH diet score and hyperuricemia was assessed using multiple logistic regression models, adjusting for age, sex, total energy, obesity, physical activity, education, smoking, alcohol drinking, blood pressure, fasting glucose, lipid profiles, renal function, and presence of cardiovascular disease., Results: A High DASH diet score was associated with low odds of having hyperuricemia (adjusted odds ratio for quartile 4 versus quartile 1 0.70 [95% confidence interval 0.66, 0.75], P for trend < 0.001) after adjusting for potential confounders. The association between the DASH diet and hyperuricemia was more pronounced among older individuals (age ≥50 years), women, and physically inactive participants compared with their counterparts (P for interaction < 0.01 for all)., Conclusion: The DASH diet was associated with a low likelihood of having hyperuricemia in Chinese adults., (© 2020, American College of Rheumatology.)

Gout, known as "the disease of the kings", is the most frequent type of arthritis. It results from sustained hyperuricemia that leads to monosodium urate crystal deposition in joint structures and soft tissue. Environmental factors such as diet affect the incidence of gout; there is a known relationship between the occurrence of an acute attack of gout and the consumption of alcohol and meat; and a low purine diet is a widely recognized nonpharmacological method of supplementing the treatment and preventing recurrence of arthritis. This review aims to summarize the current knowledge about the role of vitamin C in prevention and treatment of gout. A PubMed/Medline database search on the role of vitamin C in purine metabolism was done. Reports from in vitro and animal studies seem to be promising and to allow explanation of the physiological relationship between vitamin C and uric acid. Most epidemiological studies indicate a significant correlation between high vitamin C intake and lower serum uric acid levels. Despite promising observations, there are few observational and interventional studies, and their results do not clearly define the benefits of a high daily intake of vitamin C in preventing the development and recurrence of gout.

Context: Lycium barbarum L. (Solanaceae) polysaccharides (LBPs) are important active constituents that have demonstrated kidney protection., Objective: This study investigated the effect of LBPs on hyperuricaemia and explored the underlying mechanism in mice., Materials and Methods: Thirty-six C57BL/6 mice were randomly divided into the control group, hyperuricaemia group, allopurinol group (5 mg/kg) and three LBP groups (n = 6). The LBP groups were treated orally with LBPs at 50, 100 and 200 mg/kg body weight for 7 days. We examined the levels of serum uric acid (S UA ) and urinary uric acid (U UA ), as well as xanthine oxidase (XOD) activities. mRNA and protein were quantified by quantitative real-time PCR and Western blotting, respectively., Results: LBPs treatment (100 and 200 mg/kg) significantly reduced the S UA levels to 4.83 and 4.48 mg/dL, and markedly elevated the U UA levels to 4.68 and 5.18 mg/dL ( p  < 0.05), respectively, while significantly increased the mRNA and protein expression levels of renal organic anti-transporter 1 (OAT1) and organic anti-transporter 3 (OAT3), and markedly decreased the levels of glucose transporter 9 (GLUT9) ( p  < 0.05). Additionally, the serum XOD activities were reduced to 31.5 and 31.1 mU/mL, and the liver XOD activities were reduced to 80.6 and 75.6 mU/mL after treatment with 100 and 200 mg/kg LBPs ( p  < 0.01), respectively., Discussion and Conclusions: This study demonstrated the potential role of LBPs in reducing the uric acid level in hyperuricemic mice. A border study population should be evaluated. These results are valuable for the development of new anti-hyperuricaemia agents from LBPs.

Background The recommended dose of rasburicase is quite expensive, thus limiting its use. Whether a lower dose of rasburicase would be equally effective for critically ill children, who often have more complicated situations and a higher risk of hospital death, is still unknown. Objective To explore the safety and efficacy of low-dose rasburicase in critically ill children with haematological malignancies who are at high risk of tumour lysis syndrome. Setting A single-centre retrospective cohort study. Method Children with haematological malignancies who had a history of rasburicase exposure during an intensive care unit stay were enrolled. Patients were divided into two groups according to the initial dosage of rasburicase: the standard-dose group (> 0.1 mg/kg/day) and the low-dose group (≤ 0.1 mg/kg/day). The adverse events and short-term prognosis of the two groups were compared. Results Thirty-seven children were selected, 22 in the standard-dose group and 15 in the low-dose group. The most common tumour type was Burkitt's lymphoma (81%), followed by acute lymphoblastic leukaemia (11%). All patients were at high risk of tumour lysis syndrome, and 73% of them had 3 or more tumour lysis syndrome risk factors. The uric acid levels of 90% of patients with hyperuricaemia returned to the normal range within 12 h (100% in the standard-dose group and 75% in the low-dose group, P = 0.083). Eighty-four percent of patients presented serious complications, including tumour lysis syndrome (73%), acute kidney injury (59%), renal replacement treatment (24%), respiratory failure (24%), disseminated intravascular coagulation (16%) and heart failure (11%). There was no significant difference in the incidence of serious complications between the two groups. The overall 7-day and 28-day survival rates after intensive care unit admission were 86% and 84%, respectively. The average length of stay in the intensive care unit was 9.92 ± 5.13 days. Neither the short-term mortality nor the length of stay in the intensive care unit were significantly different between the two groups. Conclusion Low-dose rasburicase is effective and may be an acceptable choice for critically ill children with haematological malignancies.

Aim: Hyperuricemia (HUA) is a metabolic disease caused by the overproduction or underexcretion of uric acid (UA). Our previous study found that treatment with Dendrobium officinalis six nostrum (DOS) led to a significant reduction in serum UA (SUA) by inhibiting UA production and promoting UA excretion in a rat model of HUA induced by potassium oxonate (PO) and high-fat sorghum feed. In this study, we aimed to further investigate the effects of DOS on UA excretion by the kidney and intestine to explore whether DOS protects against histopathological changes, and to elucidate its possible mechanisms of action in a lipid emulsion (LE)-induced rat model of HUA., Methods: The main chemical constituents of DOS were determined to be acteoside and astilbin by high-performance liquid chromatography (HPLC). Three different doses of DOS (3.3, 6.6, and 13.2 g/kg/day) were given to rats daily after induction of HUA by oral administration of LE for 8 weeks. The levels of creatinine (Cr) in serum and urine and UA in serum, urine, and feces were measured by an automatic biochemical analyzer. The expression of TLR4, NF-κB and urate transport-related transporters (URAT1, ABCG2, and PDZK1) in kidney was measured by Western blot (WB). Intestinal urate transporters (ABCG2 and GLUT9) expression was assayed by IHC and WB. Serum LPS and renal inflammatory factors (IL-6, IL-8 and TNF-α) levels were measured using enzyme-linked immunosorbent assay (ELISA) kits. Hematoxylin and eosin (H&E) staining was used to assess renal histological changes., Results: DOS treatment significantly reduced the SUA and SCr levels by increasing urine volume, 24 h urine uric acid (UUA), fecal UA (FUA), urine creatinine (UCr), and fractional excretion of UA (FEUA) levels in hyperuricemic rats. Moreover, DOS effectively regulated URAT1, PDZK1, and ABCG2 protein levels in the kidney, as well as restored protein levels of GLUT9 and ABCG2 in the intestine. DOS markedly reduced serum LPS anddown-regulated renal TLR4 and NF-κB protein levels to suppress IL-6, IL-8, and TNF-α secretion. It also improved renal inflammation in hyperuricemic rats. In addition, DOS attenuated histopathological changes in the kidneys of LE-induced rats. HPLC analysis showed levels of acteoside and astilbin of 1.39 mg/g and 0.72 mg/g in DOS, respectively., Conclusion: DOS has anti-hyperuricemic and anti-inflammatory effects in a rat model of HUA. The molecular mechanism appears to involve the regulation of urate transport-related transporters including renal ABCG2, URAT1, and PDZK1, and intestinal GLUT9 and ABCG2, as well as the inhibition of the LPS/TLR4/NF-κB signaling to reduce IL-6, IL-8, and TNF-α secretion in hyperuricemic rats., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

This study was designed to investigate the effects and underlying mechanisms of Astaxanthin (AST) on high-fructose-induced hyperuricemia (HUA) from the perspectives of the uric acid (UA) synthesis and excretion in rat models. Following six weeks of a 10% fructose diet, the level of serum UA effectively decreased in the AST groups as compared to the model group. The enzymatic activities of xanthine oxidase (XOD) and adenosine deaminase (ADA) were significantly inhibited, and the mRNA expression levels of XOD and ADA significantly decreased after the AST administration. These results suggested that the AST reduced UA synthesis by inhibiting the mRNA expressions and enzyme activities of XOD and ADA, thereby contributing to HUA improvement. On the hand, the relative expressions of the mRNA and protein of kidney reabsorption transport proteins (GLUT9 and URAT1) were significantly down-regulated by AST, while that of the kidney secretion proteins (OAT1, OAT3 and ABCG2) were significantly up-regulated by AST. These results indicated that the AST promoted UA excretion by regulating the urate transport proteins, and thus alleviated HUA. This study suggested that the AST could serve as an effective alternative to traditional medicinal drugs for the prevention of fructose-induced HUA.

Ethnopharmacological Relevance: Herbaceous peony (Paeonia lactiflora Pall.) flower has been used widely in dietotherapy in China and other countries. It has good ethnopharmacological value in the treatment of various metabolic diseases. However, the molecular mechanisms by which it lowers serum uric acid are unknown. The development of pharmaceutical resources is very important. Here, we sought to elucidate the mode of action of herbaceous peony in terms of reducing uric acid levels., Aim of the Study: In the present research, the effects of the total glucosides of herbaceous peony flower were investigated in a rat hyperuricaemia model. Another aim of the study was to clarify the mechanism by which herbaceous peony flower (TGPF) lowers serum uric acid levels., Materials and Methods: A hyperuricaemic rat model was induced via intragastric administration of 100 mg/kg adenine and 250 mg/kg ethambutol hydrochloride (EH) for 23 d. Then TongFengShu 600 mg/kg, allopurinol 42 mg/kg, or TGPF (50 mg/kg, 100 mg/kg, or 200 mg/kg) was administered 1 h after the adenine and EH treatments., Results: TGPF improved weight loss and decreased serum UA, XOD, MCP-1, TNF-α, Cr, and BUN in the rats with hyperuricaemic nephropathy. TGPF downregulated renal URAT1 and GLUT9, upregulated renal OAT1, and ameliorated histopathological changes in the thymus, spleen, and kidney., Conclusion: TGPF is promising as a therapeutic agent against hyperuricaemia. It regulates the uric acid transporters and diminished serum uric acid levels, and alleviates renal pathology associated with hyperuricaemia., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Introduction: Osteoarthritis (OA), a chronic and degenerative joint disease characterized by articular cartilage degeneration, sclerosis of subchondral bone, and osteophyte formation, is deemed a leading cause of activity limitation and disability among the elderly people. Serum uric acid (UA) is a terminal metabolite of purine compound, while hyperuricemia (HU) and UA crystals are recognized causes of gout. Several studies have investigated the correlations between HU, gout and OA, but the findings are inconclusive. We are also concerned whether the urate lowering therapy (ULT) can become a potential treatment for OA and intend to undertake this meta-analysis to clarify the related hypotheses., Methods: Systematic literature search will be conducted on PubMed, Embase, and Web of Science to identify relevant studies up to February 2020 using appropriate search strategies. All citations and abstracts retrieved from literature search will be assessed by two reviewers independently. The Newcastle-Ottawa Scale or the Cochrane risk of bias assessment tool will be used as appropriate to assess the quality and the risk of bias of the included studies. The heterogeneity and the publication bias of the studies will be investigated accordingly., Results: We propose to undertake this meta-analysis as a feasible approach to clarify the associations between HU, gout or ULT, and OA., Discussions: This meta-analysis will help to strengthen our knowledge of the pathogenesis of OA and promote the development of preventive or treatment strategies., Registration: PROSPERO registration number CRD42020168769.

Objectives : China has already entered the aging society, and its aging population is the largest worldwide. Accordingly, several aging-related conditions including hyperuricemia are becoming a public health concern owing to their increasing prevalence in rural areas. However, the sex-specific differences in the risk factors for hyperuricemia among the middle-aged and elderly in rural North China are unclear. Thus, this study aimed to evaluate sex-specific differences in the prevalence of and risk factors for hyperuricemia in low-income adults in rural North China. Methods : This population-based cross-sectional study recruited participants aged ≥50 years from the Tianjin Brain Study between April and August 2019. After excluding those who had cancer, severe psychiatric disturbances, hepatic failure, and serious renal disease (i.e., an estimated glomerular filtration rate (eGFR) of <30 mL/min/1.73 m 2 ), 3119 (1392 men and 1727 women) eligible participants were included. Basic information and blood samples were collected, and data were analyzed using logistic regression models. Results : Hyperuricemia was prevalent in 14.4% (men, 14.2%; women, 14.5%)of the participants, and the prevalence significantly increased with increasing age in both sexes (male, P = 0.034; female, P < 0.001). In multivariate analysis, obesity, metabolic syndrome, and high levels of total cholesterol, 2 h plasma glucose, and blood urea nitrogen were risk factors for hyperuricemia in both men and women. Physical activity was a risk factor in men, while a high white blood cell count was a risk factor in women. A high eGFR was a protective factor in both sexes. Conclusions : Hyperuricemia was highly prevalent in low-income adults in Tianjin, with men and women showing differences in risk profiles and comorbidities. Early management of hyperuricemia according to sex-specific risk factors should be considered in primary care to reduce the prevalence and burden of hyperuricemia in rural China.

Background and Aims: The prevalence of hyperuricemia has increased substantially in recent decades. It has been suggested that it is an independent risk factor for weight gain, hypertension, hypertriglyceridemia, metabolic syndrome (MetS), and cardiovascular disease. Results from epidemiological studies conducted in different study populations have suggested that high consumption of dairy products is associated with a lower risk of developing hyperuricemia. However, this association is still unclear. The aim of the present study is to explore the association of the consumption of total dairy products and their subtypes with the risk of hyperuricemia in an elderly Mediterranean population with MetS., Methods and Results: Baseline cross-sectional analyses were conducted on 6329 men/women (mean age 65 years) with overweight/obesity and MetS from the PREDIMED-Plus cohort. Dairy consumption was assessed using a food frequency questionnaire. Multivariable-adjusted Cox regressions were fitted to analyze the association of quartiles of consumption of total dairy products and their subtypes with the prevalence of hyperuricemia. Participants in the upper quartile of the consumption of total dairy products (multiadjusted prevalence ratio (PR) = 0.84; 95% CI: 0.75-0.94; P-trend 0.02), low-fat dairy products (PR = 0.79; 95% CI: 0.70-0.89; P-trend <0.001), total milk (PR = 0.81; 95% CI: 0.73-0.90; P-trend<0.001), low-fat milk (PR = 0.80; 95% CI: 0.72-0.89; P-trend<0.001, respectively), low-fat yogurt (PR = 0.89; 95% CI: 0.80-0.98; P-trend 0.051), and cheese (PR = 0.86; 95% CI: 0.77-0.96; P-trend 0.003) presented a lower prevalence of hyperuricemia. Whole-fat dairy, fermented dairy, and yogurt consumption were not associated with hyperuricemia., Conclusions: High consumption of total dairy products, total milk, low-fat dairy products, low-fat milk, low-fat yogurt, and cheese is associated with a lower risk of hyperuricemia., Competing Interests: Declaration of Competing Interest Mena-Sánchez G declares no conflicts of interest. Babio N declares that she has received payments from Danone S.A. for scientific and technical consulting but not for the preparation of this study. She is one of the members of the Scientific Advisory Board of the EU program for the promotion of milk and milk products within the framework of appropriate dietary practices. Becerra-Tomás N declares no conflicts of interest. Miguel Ángel Martínez-González, Andrés Díaz-López, Dolores Corella, Maria Dolores Zomeño, Dora Romaguera, Jesús Vioque, Ángel M. Alonso-Gómez, Julia Wärnberg, J. Alfredo Martínez, Luís Serra-Majem, Ramon Estruch, Rosa Bernal, José Lapetra, Xavier Pintó, Josep A. Tur, José Lopez-Miranda, Naomi Cano-Ibáñez, Jose Juan Gaforio, Pilar Matía-Martín, Lidia Daimiel, José Luis Llisterri Caro, Josep Vidal, Clotilde Vázquez, Emili Ros, Ana Garcia Arellano, Antoni Palau, Rebeca Fernández-Carrión, Alejandra Pérez-Vega, Marga Morey, Manoli García de la Hera, Jessica Vaquero-Luna, Francisco J. Carmona-González, Itziar Abete, Jacqueline Álvarez-Pérez, Rosa Casas, José Carlos Fernández-García, José Manuel Santos-Lozano, Emili Corbella, Antoni Sureda, Miguel Ruiz Canela, Rocio Barragán, Albert Goday, Marian Martín, María Consuelo Altozano Rodado, Estefanía Toledo, Montse Fitó declare no conflicts of interest. Salas-Salvadó J reports that he has served on the Board of and received grant support through his institution from the International Nut and Dried Fruit Council; has served as a member of the Danone S.A. Advisory Board; has received personal consulting fees from Danone, Font Vella Lanjaron, Nuts for Life, and Eroski; and has received grant support through his institution from the Nut and Dried Fruit Foundation and Eroski., (Copyright © 2019 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Nanoparticles are known for their unique properties and are being utilized in various disciplines of sciences. Their nanosize enables them to higher exposure and higher availability when given orally. Gout is an inflammatory disease caused by deposition of monosodium urate (MSU) crystal deposition into the joints. The objective of this study was to evaluate the effects of copper oxide nanoparticles on hyperuricemia and gouty arthritis in mice. In this research, synthesized copper oxide nanoparticles of size ranging from 30 to 50 nm were administered orally to mice having gouty arthritis and hyperuricemia. Various biochemical markers were conducted to determine the effects of copper oxide nanoparticles. It was observed that the mice treated with CuO NPs at various concentrations showed a significant (0.001) decrease in the serum uric acid levels in comparison with the negative control. Furthermore, creatinine levels were also normal in comparison with the control mice. Measurement of synovial joints also revealed that mice administered with CuO NPs had reduced inflammation of synovial joints in comparison with the negative control. From this research, it was concluded that copper oxide nanoparticles have potential in the treatment of hyperuricemia and gouty arthritis by decreasing serum uric acid and inflammation in synovial joints.

Hyperuricemia is caused by hepatic overproduction of uric acid and/or underexcretion of urate from the kidneys and small intestine. Although increased intake of citrus fruits, a fructose-rich food, is associated with increased risk of gout in humans, hesperidin, a flavonoid naturally present in citrus fruits, reportedly reduces serum uric acid (SUA) levels by inhibiting xanthine oxidase (XOD) activity in rats. However, the effects of hesperidin on renal and intestinal urate excretion were previously unknown. In this study, we used glucosyl hesperidin (GH), which has greater bioavailability than hesperidin, to clarify comprehensive mechanisms underlying the hypouricemic effects of hesperidin in vivo. GH dose-dependently decreased SUA levels in mice with hyperuricemia induced by potassium oxonate and a fructose-rich diet, and inhibited XOD activity in the liver. GH decreased renal urate excretion without changes in kidney URAT1, ABCG2 or GLUT9 expressions, suggesting that reducing uric acid pool size by inhibiting XOD decreased renal urate excretion. We also found that GH had no effect on intestinal urate excretion or protein expression of ABCG2. Therefore, we concluded that GH exhibits a hypouricemic effect by inhibiting XOD activity in the liver without increasing renal or intestinal urate excretion. Of note, this is the first study to elucidate the effect of a flavonoid on intestinal urate excretion using a mice model, whose findings should prove useful in future food science research in the area of urate metabolism. Taking these findings together, GH may be useful for preventing hyperuricemia, especially in people with the overproduction type., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: To examine modifiable risk factors in relation to the presence of hyperuricemia and to estimate the proportion of hyperuricemia cases in the general population that could be prevented by risk factor modification, along with estimates of the variance explained., Methods: Using data obtained from 14,624 adults representative of the US civilian noninstitutionalized population, we calculated adjusted prevalence ratios for hyperuricemia, population attributable risks (PARs), and the variance explained according to the following 4 factors: body mass index (BMI; ≥25 kg/m 2 ), alcohol intake, nonadherence to a Dietary Approaches to Stop Hypertension (DASH) diet, and diuretic use., Results: BMI, alcohol intake, adherence to a DASH-style diet, and diuretic use were all associated with serum urate levels and the presence of hyperuricemia in a dose-dependent manner. The corresponding PARs of hyperuricemia cases for overweight/obesity (prevalence 60%), nonadherence to a DASH-style diet (prevalence 82%), alcohol use (prevalence 48%), and diuretic use (prevalence 8%) were 44% (95% confidence interval [95% CI] 41%, 48%), 9% (95% CI 3%, 16%), 8% (95% CI 5%, 11%), and 12% (95% CI 11%, 14%), respectively, whereas the corresponding variances explained were 8.9%, 0.1%, 0.5%, and 5.0%. Our simulation study showed the variance nearing 0% as exposure prevalence neared 100%., Conclusion: In this nationally representative study, 4 modifiable risk factors (BMI, the DASH diet, alcohol use, and diuretic use) could be used to individually account for a notable proportion of hyperuricemia cases. However, the corresponding serum urate variance explained by these risk factors was very small and paradoxically masked their high prevalences, providing real-life empirical evidence for its limitations in assessing common risk factors., (© 2019, American College of Rheumatology.)

Background: The aim was to assess the effect of estrogen-progestin therapy (EPT) on serum levels of uric acid (SUA) and its precursors xanthine (X) and hypoxanthine (HX), and on uric acid (UA) renal excretion in hypertensive postmenopausal women treated with an angiotensin-converting enzyme inhibitor (ACEI) or thiazide diuretic (HCTZ) (ClinicalTrials.gov identifier: NCT03921736, registered 19 April 2019). Methods: Postmenopausal women with untreated essential hypertension were recruited to the study. The control group consisted of 40 postmenopausal women with normal blood pressure. Hypertensive women were randomized to two groups: hydrochlorothiazide ( n  = 50) or perindopril ( n  = 50) and to a group receiving or not receiving EPT (EPT+/EPT-) due to vasomotor symptoms. The follow-up period was one year. Blood pressure measurements as well as blood tests for SUA and its precursors X and HX were performed at baseline and after 12 months. Results: In hypertensive women, baseline serum X and HX were significantly higher when compared to the group of normotensive women. Treatment with HCTZ led to a statistically significant increase in SUA in the subgroup of EPT- women. In this group concentrations of X and HX increased significantly after 12 months. UA/X significantly decreased after treatment with HCTZ. Lack of EPT resulted in a decrease of renal plasma flow in the HCTZ group. However, in the HCTZ and EPT + group, SUA decreased significantly when compared to baseline. None of these unfavorable effects was observed in the ACEI group regardless of EPT. Conclusions: 1) EPT prevents the development of hyperuricemia during antihypertensive treatment with thiazide diuretics. 2) Arterial hypertension and menopause cause impairment of UA excretion and increase the levels of SUA and its precursors X and HX. 3) EPT reduces the risk of hyperuricemia in postmenopausal women.

Current evidences suggest that hyperuricemia is closely related to the overproduction or underexcretion of uric acid (UA). Curcumin (CUR), a natural polyphenol component extracted from the rhizome of Curcuma longa, has been reported to treat various symptoms such inflammation disease, seems to be efficacious in hyperuricemia. In this study, we aimed to investigate the effect of CUR on hyperuricemia and kidney inflammation in hyperuricemic mice. Administration with CUR (20 or 40 mg/kg) or allopurinol (ALL, 5 mg/kg) was given to mice orally one hour later after the injection of potassium oxonate (PO) (300 mg/kg, i.p.) for 14 days. CUR administration decreased the levels of uric acid (UA), creatinine (CRE) and blood urea nitrogen (BUN) in serum. Meanwhile, treatment with CUR effectively inhibited serum and liver xanthine oxidase (XOD) levels, and further renewed normal antioxidant enzymes activities (SOD, GSH-Px), reduced MDA accumulation in serum. Further studies showed that CUR decreased inflammatory cytokines productions (IL-1β, IL-18) in serum, as well as inhibited PO-induced the activation of NLRP3 inflammasome signaling in the kidney. In conclusion, the study revealed that CUR exhibited anti-hyperuricemic and anti-inflammatory effects through suppressing NLRP3 inflammasome activation in kidney and provided the evidence for treating hyperuricemia and associated renal inflammation., (Copyright © 2019 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

This study reported a novel highly active alkaline urate oxidase (UOX) and demonstrated its application in reducing uric acid content of food under alkaline conditions. The UOX gene was cloned from Arxula adeninivorans NBRC 10858, and its N-terminally his 6 -tagged form (rUOX) was overexpressed in Escherichia coli. The rUOX displayed maximal activity at 40 °C and pH 10, kept more than 90% initial activity under alkaline conditions (pH 9-11) and more than 80% at temperatures below 55 °C. The apparent K m , turnover number (k cat ) and catalytic efficiency (k cat /K m ) values for the substrate uric acid were respective 29.15 µM, 151.16 s -1 and 5.19 s -1 . μM -1 , which are improvements over previously reported UOXs. The rUOX efficiently reduced uric acid and purine contents in beer, beef and yeast extract at pH 10, indicating a promising application in food with low purine and uric acid contents to prevent hyperuricemia and gout., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: A significant discovery was recently made in which participation in physical activity and sedentary behavior, two contrasting lifestyles, was found to be related to the frequency of hyperuricemia diagnosis. The purpose of this study was to identify the association between sedentary behavior and physical activity levels in South Korean men and women diagnosed with hyperuricemia., Methods: This study included 161,064 healthy men and women participants who had obtained a complete health examination. Physical activity levels and sitting time were assessed by the validated International Physical Activity Questionnaire Short Form Korean version. The presence of hyperuricemia in the subjects was determined by measuring serum uric acid (SUA) concentration (SUA ≥6 mg/dL [male], SUA ≥7 mg/dL [female]). Logistic regression analysis, adjusting other confounding factors, was conducted to identify the association of sedentary behavior and physical activity levels with hyperuricemia ( p <0.05)., Results: Subjects who spent ≥10 hr/day in sedentary behavior were more likely to have hyperuricemia than those who spent <5 hour/day in sedentary behavior (OR=1.08, 95% CI=1.03-1.12). The subject group that more frequently participated in health enhanced physical activity (HEPA) had a lower hyperuricemia odds ratio than the subject group with lower physical activity participation rate (OR=0.90, 95% Ci=0.86-0.93). From the analysis of sex (male, female), age (young, middle, older), methods of measuring obesity (body mass index, waist circumference, body fat percentage), the association of sedentary behavior and physical activity levels with hyperuricemia was shown differently in different multivariable models., Conclusion: Participation in regular physical activity and reduced sedentary time is highly recommended in order to reduce the prevalence of hyperuricemia., Competing Interests: The authors report no conflicts of interest in this work., (© 2019 Park et al.)

Plant-based diets (PBDs) are associated with decreased risk of morbidity and mortality associated with important noncommunicable chronic diseases. Similar to animal-based food sources (e.g . , meat, fish, and animal visceral organs), some plant-based food sources (e.g . , certain soy legume products, sea vegetables, and brassica vegetables) also contain a high purine load. Suboptimally designed PBDs might consequently be associated with increased uric acid levels and gout development. Here, we review the available data on this topic, with a great majority of studies showing reduced risk of hyperuricemia and gout with vegetarian (especially lacto-vegetarian) PBDs. Additionally, type of ingested purines, fiber, vitamin C, and certain lifestyle factors work in concordance to reduce uric acid generation in PBDs. Recent limited data show that even with an exclusive PBD, uric acid concentrations remain in the normal range in short- and long-term dieters. The reasonable consumption of plant foods with a higher purine content as a part of PBDs may therefore be safely tolerated in normouricemic individuals, but additional data is needed in hyperuricemic individuals, especially those with chronic kidney disease., Competing Interests: B.J. (Barbara Jakše) is receiving royalty compensation at Herbalife Nutrition. Other authors declare no conflict of interest.

The consumption of fructose has gained increased attention as a potential cause of hyperuricaemia since fructose metabolism produces urate as a byproduct. In addition to sucrose and high fructose corn syrup, fresh fruits also contain fructose, suggesting that patients with hyperuricaemia or gout might also avoid fresh fruit. However, the effect of fruits is complex. Some studies reported that fruit intake was associated with gout flares while other studies showed that fruits rather lowered the risk for gout. Thus, fruits should not be simply viewed as a source of fructose. The complexity of fruits is accounted for by several nutrients existing in fruits. Vitamin C, epicatechin, flavonols, potassium and fibre are all nutrients in fruits, and these factors could modify fructose and urate effects. In this review, we discuss clinical studies evaluating the effect of fruit and fruit juice intake on hyperuricaemia and gout, and propose potential mechanisms for how fruit may influence urate levels., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Light and Shadow of Hyperuricemia - Neuroprotection, Comorbidities and Therapeutic Strategies Abstract. Hyperuricemia can lead to gout but also favor the appearance of comorbidities like hypertension, kidney insufficiency, type 2 diabetes, myocardial infarction and strokes. Uric acid does not only have, however, negative impact on the body, but seems to influence positively certain inflammatory and degenerative neurological diseases. The inflammatory reaction at the center of a gout attack is mediated by interleukin 1. Therefore, antagonists against interleukin 1 or IL-1 receptors can be used for treatment if colchicine, steroids or nonsteroidal anti-inflammatory drugs are ineffective or contraindicated. First-line drug for urate-lowering therapy is allopurinol that positively influences comorbidities as well.

Extracellular signal-regulated kinases 1 and 2 (ERK1/2) are serine/threonine kinases and function as regulators of cellular proliferation and differentiation. Recently, we demonstrated that inhibition of ERK1/2 alleviates the development and progression of hyperuricemia nephropathy (HN). However, its potential roles in uric acid-induced tubular epithelial-mesenchymal transition (EMT) and tubular epithelial cell injury are unknown. In this study, we showed that hyperuricemic injury induced EMT as characterized by downregulation of E-cadherin and upregulation of vimentin and Snail1 in a rat model of HN. This was coincident with epithelial cells arrested at the G 2 /M phase of cell cycle, activation of Notch1/Jagged-1 and Wnt/β-catenin signaling pathways, and upregulation of matrix metalloproteinase-2 (MMP-2) and MMP-9. Administration of U0126, a selective inhibitor of ERK1/2, blocked all these responses. U0126 was also effective in inhibiting renal tubular cell injury, as shown by decreased expression of lipocalin-2 and kidney injury molecule-1 and active forms of caspase-3. U0126 or ERK1/2 siRNA can inhibit tubular cell EMT and cell apoptosis as characterized with decreased expression of cleaved caspase-3. Moreover, ERK1/2 inhibition suppressed hyperuricemic injury-induced oxidative stress as indicated by decreased malondialdehyde and increased superoxide dismutase. Collectively, ERK1/2 inhibition-elicited renal protection is associated with inhibition of EMT through inactivation of multiple signaling pathways and matrix metalloproteinases, as well as attenuation of renal tubule injury by enhancing cellular resistance to oxidative stress.

Background: Clinical studies have shown that bipolar patients have increased serum uric acid levels. High serum uric acid levels could play a role contributing to high prevalence of metabolic syndrome. Metabolic syndrome is known to increase the risk of developing a number of life threatening diseases including coronary heart disease, hypertension, and type 2 diabetes. This study investigated the association between hyperuricemia and metabolic syndrome and its components in individuals suffering from bipolar disorders., Methods: This study recruited 318 inpatients suffering from bipolar disorders from Beijing Hui-Long-Guan Hospital in China and 160 healthy subjects from the same region as the controls. We used National Cholesterol Education Program Adult Treatment Panel III Adapted criteria (NCEP ATP-III A) for the diagnosis of metabolic syndrome. Hyperuricemia was determined as serum uric acid level above 420 μmol/L in men and 360 μmol/L in women (N Engl J Med 359(17):1811-1821, 2008)., Results: Among 318 bipolar patients, there was higher prevalence of metabolic syndrome (42.5%) and hyperuricemia (27.7%) than healthy controls (21.9 and 11.9%). Bipolar patients with metabolic syndrome had increased prevalence of hyperuricemia (OR = 3.0, CI95 [1.7-5.4]). Hypertriglyceridemia and larger waist circumference (WC) were associated with hyperunicemia (OR = 1.8, CI95 [1.1-3.1], OR = 1.9, CI95 [1.1-3.4]). Hyperuricemia was associated with metabolic syndrome in bipolar patients (p < 0.001) and especially with hypertriglyceridemia (OR = 1.9, CI95 [1.1-3.1] and increased WC (OR = 2.1 [1.2-4.0]). Bipolar patients over 50 years of age and hyperuricemia were highly prone to develop metabolic syndrome (OR = 14.0, CI95 [5.0-39.0])., Conclusions: Hyperuricemia was highly associated with development of metabolic disorder particularly for aged patients suffering from bipolar disorders. Early prevention of hyperuricemia and metabolic syndrome may lead better life for bipolar patients when they get older.

Background and Objectives: Recent studies have shown that hyperuricemia is commonly associated with dyslipidemia, cardiovascular diseases, hypertension and metabolic syndrome. Elevated serum uric acid has been demonstrated to be associated with obesity in the adult population in many countries; however, there is still a lack of evidence for the Bangladeshi population. The aims of this study were to evaluate the prevalence of hyperuricemia and determine the relationship between serum uric acid (SUA) and obesity among the Bangladeshi adults., Methods: In this cross-sectional study, blood samples were collected from 260 adults (142 males and 118 females) and analyzed for SUA and lipid profile. All participants were categorized as underweight (n = 11), normal (n = 66), overweight (n = 120) and obese (n = 63) according to the body mass index (BMI) scale for the Asian population. Based on SUA concentration the participants were stratified into four quartiles (Q1: < 232 μmol/L, Q2: 232-291 μmol/L, Q3: 292-345 μmol/L and Q4: > 345 μmol/L)., Results: The mean age and BMI of the participants were 32.5 ± 13.3 years and 24.9 ± 3.8 kg/m2, respectively. The average level of SUA was 294 ± 90 μmol/L with a significant difference between males and females (p < 0.001). Overall, the estimated prevalence of hyperuricemia was 9.3% with 8.4% in male and 10.2% in female participants. There were significant increases in the prevalence of obesity (17.4%, 22.2%, 28.6% and 31.8%, respectively, p < 0.01 for trend) across the SUA quartiles. A multiple logistic regression analysis revealed that SUA quartiles were independently associated with the presence of obesity (p < 0.01)., Conclusion: Present study indicates a significant positive relationship between SUA and obesity among the Bangladeshi adults. Therefore, routine measurement of SUA is recommended in obese individuals to prevent hyperuricemia and its related complications., Competing Interests: The authors have declared that no competing interests exist.

Background: Hyperuricemia (HU) is in the causal pathway for developing clinical gout. There are few population-based assessments of the absolute and relative risk of clinically diagnosed incident gout in subjects with HU. We aimed to explore the long-term risk of developing incident gout among asymptomatic adults with different levels of serum urate (SU)., Methods: Malmö Preventive Project was a population-based screening program for cardiovascular risk factors, alcohol abuse, and breast cancer in Malmö, Sweden. The study population was screened between 1974 and 1992. At baseline, subjects were assessed with a questionnaire, physical examination, and laboratory tests. Follow-up ended at first gout diagnosis, death, moving from area, or December 31, 2014. Incident gout (using ICD10 codes) was diagnosed based on national registers for specialized inpatient and outpatient care, and from 1998 onward in the Skåne Healthcare Register including primary healthcare. Incidence rates, absolute risk, hazard ratios (HRs) and potentially associated factors were analyzed by baseline SU levels, i.e. normal levels (≤ 360 μmol/L); 361-405 (levels below tissue solubility of SU), and > 405 (HU), overall, and by sex., Results: Overall, 1275 individuals [3.8%; 1014 men (4.5%) and 261 women (2.4%)] of the 33,346 study participants (mean age: 45.7 (SD: 7.4), 67% men), developed incident gout during follow-up (mean 28.2 years). Of those with HU, 14.7% of men and 19.5% of women developed gout. Compared to subjects in the lowest SU category, the age-adjusted HR in men increased from 2.7 to 6.4, and in women from 4.4 to 13.1 with increasing baseline SU category, and with a statistically significant interaction of sex (p < 0.001). Body mass index, estimated glomerular filtration rate (negative), triglycerides, alcohol risk behavior (only in men), and comorbidities such as hypertension, cardiovascular disease, and diabetes were strongly associated with SU at baseline in both sexes., Conclusions: The absolute risk for developing clinically diagnosed gout over 30 years in middle-aged subjects was 3.8%, and increased progressively in both men and women in relation to baseline SU. This risk increase was significantly higher in women than in men, whereas the associations between baseline risk markers and SU levels were similar in both sexes.

Hyperuricemia is highly prevalent and especially common in subjects with metabolic, cardiovascular and renal diseases. In chronic kidney disease, hyperuricemia is extremely common, and uric acid (UA) excretion relies on gut uricolysis by gut microbiota. Current therapy for lowering serum UA includes drugs that may produce undesired secondary effects. Therefore, this pilot study was designed to evaluate the potential of two probiotic supplements to reduce systemic uric acid concentrations. Secondary objectives were to assess whether the hypouricemic effect related to a therapeutic benefit on the hyperuricemia-induced renal damage and hypertension. Analysis of fecal microbiota was also performed. Groups of 6 rats each were followed for 5 weeks and allocated in the following treatment groups: C = Control; HU-ND = Oxonic acid-induced hyperuricemia (HU) +regular diet; HU-P = HU+placebo; HU-F1 = HU+ probiotics formula 1 and HU-F2 = HU+ probiotics formula 2. We confirmed that oxonic acid-induced hyperuricemia produced hypertension and renal functional and structural changes, along with modest changes in the overall composition of fecal microbiota. Both probiotic-containing diets prevented HU, elevated UA urinary excretion and intrarenal UA accumulation induced by oxonic acid. The hypouricemic effect conferred by probiotic supplementation also prevented the renal changes and hypertension caused by hyperuricemia. However, probiotic treatment did not restore the fecal microbiota. In conclusion, we demonstrated for the first time the ability of probiotics containing uricolytic bacteria to lower serum uric acid in hyperuricemic animals with beneficial consequences on blood pressure and renal disease. As probiotics supplements are innocuous for human health, we recommend clinical studies to test if probiotic supplements could benefit hyperuricemic individuals., Competing Interests: The authors of this manuscript have the following competing interests: NR, PR, UV and AI work for Kibow Biotech. RJJ is an inventor on patents related to lowering uric acid as it relates to BP, insulin resistance, and diabetic kidney disease and has equity in XORT Therapeutics, Inc and Colorado Research Partners LLC, which are startup companies interested in developing novel xanthine oxidase inhibitors and fructokinase inhibitors, respectively. Dr. Johnson has also received honoraria from Danone and Astra Zeneca and is on the Scientific Board of Kibow, Inc. LGSL receives research support from Relburn Metabolomics and Danone Research Institute and is member of Colorado Research Partners, LLC. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Tetragonia tetragonoides (Pall.) Kuntze, called New Zealand spinach (NZS), is an edible plant used in salad in Western countries and has been used to treat gastrointestinal diseases in traditional medicine. We examined the anti-obesity and anti-hyperuricemic effects of NZS and the underlying mechanisms in high-fat diet (HFD)-induced obese mice. Mice were fed a normal-fat diet (NFD); high-fat diet (HFD); HFD with 75, 150, or 300 mg/kg NZS extract; or 245 mg/kg Garcinia cambogia (GC) extract. NZS decreased body weight gain, total white adipose tissue (WAT), liver weight, and size of adipocytes and improved hepatic and plasma lipid profiles. With NZS, the plasma levels of the leptin and uric acid were significantly decreased while the levels of the adiponectin were increased. Furthermore, NZS decreased the expression levels of adipogenesis-related genes and xanthine oxidoreductase (XOR), which is involved in uric acid production, while increasing that of proteins associated with fatty acid oxidation. UPLC analysis revealed that NZS contained 6-methoxykaempferol-3- O -β-d-glucosyl(1'''→2'')-β-d-glucopyranoside, 6-methoxykaempferol-3- O -β-d-glucosyl(1'''→2'')-β-d-glucopyranosyl-(6''''-caffeoyl)-7- O -β-d-glucopyranoside, and 6,4'-dimethoxykaempferol-3- O -β-d-glucosyl(1'''→2'')-β-d-glucopyranosyl-(6''''-caffeoyl)-7- O -β-d-glucopyranoside. These results suggest that NZS exerts anti-obesity, anti-hyperlipidemia, and anti-hyperuricemic effects in HFD-induced obese mice, which are partly explained by regulation of lipid-metabolism-related genes and proteins and decreased expression of XOR.

Adlay bran free phenolic extract has been previously demonstrated to possess potent xanthine oxidase (XOD) inhibitory activity. The aims of this study were to characterize the free phenolic profile of adlay bran and investigate the structure-activity relationship, underlying mechanism and interaction of phenolic acids as XOD inhibitors. A total of twenty phenolics including ten phenolic acids, two coumarins, two phenolic aldedhyes and six flavonoids were identified in a phenolic compound-guided separation by UPLC-QTOF-MS/MS. Adlay bran free phenolic extract possessed strong XOD inhibitory activity related to hydroxycinnamic acids with methoxyl groups. The hydrogen bonding and hydrophobic interactions were the main forces in the binding of adlay phenolics to XOD. Sinapic acid, identified in adlay bran for the first time, possessed strong XOD inhibitory activity in a mixed non-competitive manner, and synergistic effects with other adlay phenolic acids at low concentrations, and would be a promising agent for preventing and treating hyperuricemia., (Copyright © 2018. Published by Elsevier Ltd.)

Recent preclinical and clinical evidence suggests that hyperuricemia (HU) is an independent risk factor for metabolic syndrome, hypertension, cardiovascular disease and chronic kidney disease. Receptor-interacting protein 3 (RIP3) is an important contributor in inducing programmed necrosis, representing a newly identified mechanism of cell death combining features of both apoptosis and necrosis. In our study, RIP3 was strongly expressed in mice with hyperuricemia. RIP3 deficiency attenuated hyperuricemia in mice, evidenced by reduced serum uric acid and creatinine and enhanced urinary uric acid and creatinine, as well as the improved histological alterations in renal sections. Additionally, RIP3-deletion reduced malondialdehyde (MDA), H 2 O 2 and O 2 - , whereas enhanced superoxide dismutase (SOD), GSH and GSH-Px levels in potassium oxonate-induced mice. Potassium oxonate-treated mice showed significantly high mRNA levels of ATP-binding cassette, subfamily G, membrane 2 (ABCG2), organic anion transporter 1 (OAT1), OAT3, organic cation transporter 1 (OCT1) and organic cation/carnitine transporter 1 (OCTN1) in renal tissue samples, which were reversed by RIP3-deficiency. Meanwhile, down-regulation of circulating and kidney pro-inflammatory cytokines (IL-1β, TNF-α and IL-6) were observed in RIP3-knockout mice with hyperuricemia, associated with inactivation of toll-like receptor 4 (TLR4), inhibitor of NF-κB alpha (IκBα) and nuclear factor kappa B (NF-κB). NLR family, pyrin domain-containing 3 (NLRP3) inflammasome was also suppressed by RIP3 knockout in potassium oxonate-treated mice. Importantly, RIP3-knockout mice exhibited the decrease of FAS-associated protein with a death domain (FADD), cleaved Caspase-8/-3 and Poly (ADP-ribose) polymerase (PARP) in renal samples, along with TUNEL reduction in mice with hyperuricemia. Similar results were observed in uric acid-incubated cells with RIP3 knockdown. Thus, we suggested that RIP3 played an important role in mice with hyperuricemia, which might be a novel signal pathway targeting for therapeutic strategies in future., (Copyright © 2018. Published by Elsevier Masson SAS.)

To assess the association between dietary magnesium intake and hyperuricemia in United States (US) adults, we extracted 26,796 US adults aged 20-85 years from the National Health and Nutrition Examination Survey (NHANES) in 2001-2014. All dietary intake was measured through 24 h dietary recall method. Multivariable logistic regression analysis was performed to investigate the association between magnesium intake and hyperuricemia after adjusting for several important confounding variables. When compared to the lowest quintile (Q1), for male, adjusted odds ratios (ORs) of hyperuricemia in the second quintile (Q2) to the fifth quintile (Q5) of the magnesium intake were 0.83 (95% CI: 0.72-0.95), 0.74 (0.64-0.85), 0.78 (0.67-0.90), and 0.70 (0.58-0.84, p for trend = 0.0003), respectively. For female, OR was 0.75 (0.62-0.90) in the fourth quintile (Q4) ( p for trend = 0.0242). As compared to Q4 of magnesium intake (contains recommended amount), the relative odds of hyperuricemia were increased by 1.29 times in Q1 (OR = 1.29, 1.11-1.50) in male. The ORs were 1.33 (1.11-1.61) in Q1, 1.27 (1.07-1.50) in Q2 in female. Our results indicated that increased magnesium intake was associated with decreased hyperuricemia risk. It also indicated the importance of recommended dietary allowance (RDA) of magnesium and the potential function of magnesium intake in the prevention of hyperuricemia., Competing Interests: The authors declare no conflict of interest.

Background: Dapagliflozin inhibits the sodium-glucose-linked transporter 2 in the renal proximal tubule, thereby promoting glycosuria to reduce hyperglycemia in type 2 diabetes mellitus. Because these patients may require loop diuretics, and sodium-glucose-linked transporter 2 inhibition causes an osmotic diuresis, we evaluated the diuretic interaction between dapagliflozin and bumetanide., Methods and Results: Healthy subjects (n=42) receiving a fixed diet with ≈110 mmol·d -1 of Na + were randomized to bumetanide (1 mg·d -1 ), dapagliflozin (10 mg·d -1 ), or both for 7 days, followed by 7 days of both. There were no meaningful pharmacokinetic interactions. Na + excretion increased modestly with the first dose of dapagliflozin (22±6 mmol·d -1 ; P <0.005) but by more ( P <0.005) with the first dose of bumetanide (74±7 mmol·d -1 ; P <0.005), which was not significantly different from both diuretics together (80±5 mmol·d -1 ; P <0.005). However, Na + excretion with dapagliflozin was 190% greater ( P <0.005) when added after 1 week of bumetanide (64±6 mmol·d -1 ), and Na + excretion with bumetanide was 36% greater ( P <0.005) when added after 1 week of dapagliflozin (101±8 mmol·d -1 ). Serum urate was increased 4% by bumetanide but reduced 40% by dapagliflozin or 20% by combined therapy ( P <0.05)., Conclusions: First-dose Na + excretion with bumetanide and dapagliflozin is not additive, but the weekly administration of one diuretic enhances the initial Na + excretion with the other, thereby demonstrating mutual adaptive natriuretic synergy. Combined therapy reverses bumetanide-induced hyperuricemia. This requires further study in diabetic patients with hyperglycemia who have enhanced glycosuria and natriuresis with dapagliflozin., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00930865., (© 2018 The Authors and AstraZeneca. Published on behalf of the American Heart Association, Inc., by Wiley.)

Scope: We aimed examining apple polyphenols' effect on uricemia and endothelial function in a sample of overweight subjects., Methods and Results: This was a two-phased study. In vitro experiment aimed to evaluate apple polyphenols' ability to lower uric acid in comparison with allopurinol. In vivo study consisted in a randomized, double-blind, parallel placebo-controlled clinical trial involving 62 overweight volunteers with suboptimal values of fasting plasma glucose (100 mg/dL≤FPG≤125 mg/dL), randomized to 300 mg apple polyphenols or placebo for 8 weeks. Apple polyphenols extract inhibited xanthine oxidase activity, with an IC50 = 130 ± 30 ng/mL; reducing uric acid production with an IC50 = 154 ± 28 ng/mL. During the trial, after the first 4 weeks of treatment, FPG decreased in the active treated group (-6.1%, p < 0.05), while no significant changes were observed regarding the other hematochemistry parameters. After 4 more weeks of treatment, active-treated patients had an improvement in FPG compared to baseline (-10.3%, p < 0,001) and the placebo group (p < 0,001). Uric acid (-14.0%, p < 0.05 versus baseline; p < 0.05 versus placebo) and endothelial reactivity (0.24±0.09, p = 0.009 versus baseline; p < 0.05 versus placebo) significantly improved too., Conclusion: In vivo, apple polyphenols extract has a positive effect on vascular oxidative stress and endothelium function and reduce FPG and uric acid by inhibiting xanthine oxidase, as our In vitro experiment attests., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Cudrania tricuspidata Bureau (Moraceae) shows numerous pharmacological effects and has been used in traditional herbal remedies for inflammation, gastritis, tumors, and liver diseases. However, no validated analytical method for the standardization and optimization of the biological properties of C. tricuspidata preparations has been reported. We developed and validated a reverse-phase high-performance liquid chromatography (HPLC) method for the separation and quantification of active markers. Ethanolic extracts of C. tricuspidata leaves were prepared and evaluated for chemical profiles and biological activities. The 80% ethanolic extract demonstrated the greatest antioxidant activity and phenolic content, while the 100% ethanolic extract had the greatest total flavonoid content and xanthine oxidase (XO) inhibitory activity. The validated HPLC method confirmed that chlorogenic acid, rutin, and kaempferol were present in C. tricuspidata leaf extracts. We postulated that the antioxidant and anti-hyperuricemic/gout effects of C. tricuspidata extract could be attributed to these marker compounds. Our results suggested that the flavonoid-rich fraction of the leaf extract may be utilized for the treatment and prevention of hyperuricemia-related diseases, and the validated method and marker compounds could be applied for the quality control of C. tricuspidata preparations., Competing Interests: The authors declare no conflict of interest.

Hyperuricemia has been linked to metabolic syndrome, cardiovascular disease, and chronic kidney disease. Hyperuricemia and type 2 diabetes mellitus were inter-related, type 2 diabetes mellitus was more at risk of having a higher serum uric acid level, and also individuals with higher serum uric acid had higher risk of developing type 2 diabetes in the future. Insulin resistance seems to play an important role in the causal relationship between metabolic syndrome, type 2 diabetes, and hyperuricemia. Oral diabetic drugs that would have additional beneficial effects on reducing serum uric acid levels are of importance. Selective SGLT2 inhibitors were extensively studied in type 2 diabetes mellitus and were found to have improvement of glycemic control, in addition to their proven metabolic effects on weight and blood pressure. Additional beneficial effect of SGLT2 inhibitors on serum uric acid level reduction is investigated. Recently, data have been accumulating showing that they have additional beneficial effects on serum uric acid reduction. As for the postulated mechanism, serum uric acid decreased in SGLT2 inhibitor users as a result of the increase in the urinary excretion rate of uric acid, due to the inhibition of uric acid reabsorption mediated by the effect of the drug on the GLUT9 isoform 2, located at the collecting duct of the renal tubule.

Baicalein, a natural flavonoid, is structurally advantageous for binding to xanthine oxidoreductase. In our study, molecular docking analysis and Surface Plasmon Resonance revealed a direct interaction between baicalein and xanthine oxidoreductase. Moreover, 50 mg/kg/d baicalein treatment significantly suppressed the viability of xanthine oxidoreductase in hyperuricemia mouse model. The data showed that baicalein remarkably prevented renal dysfunction, ameliorated kidney fibrosis, alleviated epithelial-mesenchymal transition and oxidative stress in hyperuricemia mice. Thus, we concluded that baicalein executed a kidney-protection action in hyperuricemia and therefore may be used as a therapeutic alternative for hyperuricemic nephropathy.

Background: The ability of antihyperuricemic therapy to exert renoprotective effects in patients with chronic kidney disease (CKD) is controversial. In the present study, we studied patient characteristics that may mask favorable impact of antihyperuricemic therapy on the progression of CKD., Methods: This was a single-center, retrospective, follow-up study. One-hundred and seventy-eight CKD patients with hyperuricemia who received febuxostat therapy were included in this study. Mean serum uric acid (mUA) level after treatment and changes in estimated glomerular filtration rate (ΔeGFR) over 6 months were measured and their correlation was examined. Patients were divided into two groups based on mUA, and their ΔeGFR were compared. These analyses were evaluated in various subgroups., Results: Febuxostat therapy markedly decreased UA level in any CKD stage patients without resulting in serious adverse events. eGFRs of CKD patients in the mUA < 6.0 mg/dl group were maintained, whereas those in the mUA ≥ 6.0 mg/dl group decreased. A significant inverse correlation was observed between mUA and ΔeGFR (r = -0.16, p = 0.019). The renoprotective effects of febuxostat were significant in the following subgroups: male patients, age < 70 years, systolic blood pressure < 130 mmHg, normal cholesterol levels, and absence of diabetes. Coexisting vascular risk factors appear to exert additive masking effects against febuxostat renoprotection., Conclusions: The results of this study suggest that various vascular risk factors markedly attenuate the renoprotective effects of febuxostat.

Hyperuricaemia is a common clinical condition that can be defined as a serum uric acid level >6.8 mg/dl (404 µmol/l). Gout, a recognized complication of hyperuricaemia, is the most common inflammatory arthritis in adults. Drug-induced hyperuricaemia and gout present an emergent and increasingly prevalent problem in clinical practice. Diuretics are one of the most important causes of secondary hyperuricaemia. Drugs raise serum uric acid level by an increase of uric acid reabsorption and/or decrease in uric acid secretion. Several drugs may also increase uric acid production. In this review, drugs leading to hyperuricaemia are summarized with regard to their mechanism of action and clinical significance. Increased awareness of drugs that can induce hyperuricaemia and gout, and monitoring and prevention are key elements for reducing the morbidity related to drug-induced hyperuricaemia and gout., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)