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Background: Simiao pill module (SMM), a traditional Chinese medicine formula, has been widely used to treat gout and gouty arthritis. The goal of this study was to investigate the effects of SMM on epithelial-mesenchymal transition (EMT) and activation of NLR family pyrin domain containing 3 (NLRP3) inflammasome in a mouse model of potassium oxonate (PO)-induced chronic hyperuricemic nephropathy (HN)., Methods: Mice were randomly divided into the following four groups: control, HN model (PO), febuxostat (FEB)-treated (PO + FEB), and SMM-treated (PO + SMM) groups. Following 6 weeks of treatment, blood samples were collected and mice were sacrificed to collect kidney samples to study the biochemical parameters associated with renal function and histopathological changes associated with HN, respectively. The samples were analyzed for the expression of markers of EMT (collagen type 3, α-smooth muscle actin [α-SMA], fibronectin, vimentin and E-cadherin) and activation of NLRP3 inflammasome (NLRP3, apoptosis-associated speck-like protein [ASC], caspase-1, interleukin [IL]-1β, and IL-18)., Results: Our results showed that hyperuricemia, impaired kidney function, and renal pathological characteristics induced by PO treatment were improved following treatment with SMM and FEB. Additionally, treatment with SMM and FEB decreased the expression of vimentin, collagen 3, fibronectin, and α-SMA, and increased the expression of E-cadherin. Moreover, NLRP3 inflammasome activation, as assessed by the increased expression of NLRP3, ASC, and caspase-1, and secretion of IL-1β and IL-18, was inhibited by treatment with SMM and FEB., Conclusion: These results suggest that SMM inhibited EMT and NLRP3 inflammasome activation in chronic HN mice, and the beneficial effect of SMM was compared with a standard drug, FEB., (© 2022. The Author(s).)

As a tropical medicinal plant, Sonneratia apetala is mainly distributed in the southeast coastal areas of China. Recently, the hypouricemic effect of Sonneratia apetala leaves and branches (SAL) has been reported, but the active compound and its mechanism are unclear. Thus, this study aims to explore the effective fraction of SAL and the mechanism of its active compound on uric acid formation and excretion. SAL was extracted with ethyl acetate and concentrated to obtain solvent-free extracts (SAL-EA). The remains fraction (SAL-E) and the supernatant fraction (SAL-S) of SAL resulting from water extraction and alcohol precipitation were collected and dried. The effects of different fractions were explored on hyperuricemic mice. SAL-S showed excellent activities in decreasing the levels of uric acid (UA), blood urea nitrogen (BUN), and creatinine (CRE) in serum and in attenuating kidney damage. Then, the active compound gallic acid (GA) identified by HPLC was assayed for its mechanism of regulating uric acid metabolism in hyperuricemic mice. The hypouricemic effect of GA was probably associated with the downregulation of URAT1 and GLUT9, upregulation of ABCG2 and decreased activities of adenosine deaminase (ADA) and xanthine oxidase (XOD). Moreover, GA suppressed the level of MDA, IL-6, IL-1β, TNF-α, TGF-β1, COX-2 and cystatin-C (Cys-C), and enhanced the activities of SOD, GSH-Px, CAT, and Na + -K + -ATPase (NKA) in the kidneys. These results indicated that GA protects against hyperuricemia-induced kidney injury via suppressing oxidative stress and inflammation as well as decreasing the serum levels of UA by regulating urate transporters.

Aims: High-fructose intake (HF) represents an inducible risk factor for non-alcoholic fatty liver disease (NAFLD). Present study aimed to illustrate the effect of HF diet (HFD) on the induction of NAFLD, hyperuricemia and role of ellagic acid as modulator., Main Methods: Twenty-four adult male albino rats were randomly divided into four groups (6/each). The first group received normal chow diet only while the others received 60 % HFD for 4 weeks and subdivided later into 3 groups. The first and second groups received allopurinol and ellagic acid, respectively while the third group received HFD only for extra 4 weeks., Key Findings: Rats fed on HFD for 8 weeks displayed body weight gain, insulin resistance (IR), hyperglycemia, dyslipidemia, hyperuricemia with increased oxidative stress and hepatic lipogenic enzymes such as ATP citrate lyase (ACL), aldolase B, and fatty acid synthase (FAS), sterol regulatory element-binding protein 1 (SERBP-1c). C1q /tumor necrosis factor-related protein -3 (CTRP3), and phosphorylated AMP-activated protein kinase (p-AMPK) however showed significant decreases. Ellagic acid or allopurinol administration significantly decreased serum lipids, uric acid, glucose, insulin levels and hepatic contents of enzymes. Malondialdehyde (MDA), FAS, aldolase B, SERBP-1c, and xanthine oxidase (XO) hepatic contents showed significant decreases along with glutathione (GSH) increase as compared to fructose group where ellagic acid was more remarkable compared with allopurinol., Significance: Our findings indicated that ellagic acid had alleviated HFD-induced hyperuricemia, its associated NAFLD pattern as mediated through activation of CTRP3 and inhibition of ACL activities in a pattern more remarkable than allopurinol., (Copyright © 2022. Published by Elsevier Inc.)

Hyperuricemia can induce acute and chronic kidney damage, but the pathological mechanism remains unclear. The potential role of AMP-activated protein kinase (AMPK) α2 in hyperuricemia-induced renal injury was investigated in this study. Acute and chronic hyperuricemic nephropathy was induced by administering intraperitoneal injections of uric acid and oxonic acid to AMPK α2 knockout and wild-type mice. Changes in renal function, histopathology, inflammatory cell infiltration, renal interstitial fibrosis, and urate deposition were analyzed. In both acute and chronic hyperuricemic nephropathy mouse models, knockout of AMPK α2 significantly reduced serum creatinine levels and renal pathological changes. The tubular expression of kidney injury molecule-1 was also reduced in hyperuricemic nephropathy mice deficient in AMPK α2. In addition, knockout of AMPK α2 significantly suppressed the infiltration of renal macrophages and progression of renal interstitial fibrosis in mice with chronic hyperuricemic nephropathy. Knockout of AMPK α2 reduced renal urate crystal deposition, probably through increasing the expression of the uric acid transporter, multidrug resistance protein 4. In summary, AMPK α2 is involved in acute and chronic hyperuricemia-induced kidney injury and may be associated with increased urate crystal deposition in the kidney., (© 2022. The Author(s).)

In health-care, there is a need to quantify medical errors. Among these errors, we observe wrong dose prescriptions. Drug dose titration (DT) is the process by which dosage is progressively adjusted to the patient till a steady dose is reached. Depending on the clinical disease, drug, and patient condition, dose titration can follow different procedures. Once modeled, these procedures can serve for clinical homogenization, standardization, decision support and retrospective analysis. Here, we propose a language to model dose titration procedures. The language was used to formalize one- and two-drug titration of chronic and acute cases, and to perform retrospective analysis of the drug titration processes on 253 patients diagnosed of diabetes mellitus type 2 and treated with metformin, 321 patients treated of chonic heart failure with furosemide, 155 patients with hyperuricemia treated with allopurinol as initial drug and febuxostat as alternative drug, and 187 hyperuricemia patients with primary drug allopurinol and supplementary drug probenecid, in order to identify different types of drug titration deviations from standard DT methods., Competing Interests: Declaration of competing interest Authors declare no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Hyperuricemia represents a risk factor for the progression of chronic kidney disease. Oxidative stress and inflammation are implicated in the mechanisms underlying hyperuricemia-mediated kidney injury. Monolluma quadrangula possesses several beneficial effects; however, its effect on hyperuricemia has not been investigated. This study evaluated the renoprotective and xanthine oxidase (XO) inhibitory activity of M. quadrangula in hyperuricemic rats. Phytochemical investigation revealed the presence of six known flavonoid isolated for the first time from this species. The rats received M. quadrangula extract (MQE) and potassium oxonate (PO) for 7 days. In vitro assays showed the radical scavenging and XO inhibitory activities of MQE, and in silico molecular docking revealed the inhibitory activity of the isolated flavonoids towards XO. Hyperuricemic rats showed elevated serum uric acid, creatinine, urea, and XO activity, and renal pro-inflammatory cytokines, MDA and NO, and decreased GSH, SOD, and catalase. MQE ameliorated serum uric acid, urea, creatinine, and XO activity, and renal pro-inflammatory cytokines. In addition, MQE attenuated renal oxidative stress, enhanced antioxidants, downregulated URAT-1, and GLUT-9 and upregulated OAT-1 in PO-induced rats. In conclusion, M. quadrangula attenuated hyperuricemia and kidney impairment by suppressing XO activity, oxidative stress and inflammation, and modulating urate transporters., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Hyperuricemia is an independent hazard factor of renal injury and can induce renal fibrosis, promoting the development of chronic kidney disease (CKD). This study aimed to explore the probability of chlorogenic acid (CGA) as a potential substance for preventing hyperuricemia nephropathy (HN). Pretreatment with CGA downregulated SUA, BUN, and CR levels, relieved oxidative stress and inflammatory response, alleviated kidney fibrosis, and contributed to the prevention of HN. In the gut microbiota, Blautia , Enterococcus , and Faecalibaculum related to trimethylamine N-oxide (TMAO) synthesis were significantly increased in HN rats. In addition, it showed a significant increase in serum TMAO content in HN rats. However, CGA regulated the cascade response of the microbiota-TMAO signaling to reverse the increase of serum TMAO. CGA also decreased the protein expression of protein kinase B (AKT) phosphorylation, phosphatidylinositide 3-kinase (PI3K), and mammalian target of rapamycin (mTOR) by reducing the production of TMAO. CGA delayed kidney fibrosis in HN rats as evidenced by regulating the cascade response of the microbiota-TMAO-PI3K/AKT/mTOR signaling pathway. In summary, CGA can be an excellent candidate for HN prevention.

Corni fructus is consumed as food and herbal medicine in Chinese culture. Studies have revealed that corni fructus exhibits potent antioxidant activity; however, few studies have investigated the ability of corni fructus to lower uric acid concentrations. In this study, the xanthine oxidase (XO) inhibition and uric acid-lowering effect of corni fructus extract (CFE) were evaluated in mice with potassium oxonate-induced hyperuricemia. Hyperuricemia is a chronic disease prevalent worldwide and is associated with high recurrence rates. In addition, drugs used to treat hyperuricemia induce side effects that discourage patient compliance. Hyperuricemia induces metabolic imbalances resulting in accumulative uric acid deposition in the joints and soft tissues. Hyperuricemia not only induces gout but also interrupts hepatic and renal function, thereby trigging severe inflammation and various complications, including obesity, nonalcoholic fatty liver disease, diabetes, and metabolic diseases. In this study, the ethyl acetate fraction (EAF) of CFE resulted in yields of antioxidant photochemical components significantly higher than those of CFEs formed using other substances. The EAF of CFE exhibited high free radical scavenging activity and XO inhibition and effectively lowered uric acid concentrations in the animal model of chemically induced hyperuricemia. The results of this study can serve as a reference for the prevention of preclinical gout as well as for functional food research.

Silver oxide nanoparticles (AgO-NPs) antioxidant, anti-cancer, anti-microbial, and tissue repair properties. Gouty arthritis is the inflammation of tissues and joints caused by the deposition of monosodium urate crystals. In this experiment, we investigated the anti-hyperuricemic effectiveness of different concentrations of AgO-NPs in mice. The present study aimed to investigate the effect of administration of AgO-NPs in monosodium urate (MSU)-induced gouty mice for the very first time. Monosodium urate (MSU) crystals were administered intraperitoneal for gout induction, followed by 5, 10, and 20 µg/mL doses of AgO-NPs for 2 weeks. The positive control was provided with the commercially available drug allopurinol to compare the effects of AgO-NPs and allopurinol. The main purpose of the study was to investigate the effectiveness of the nanoparticles in comparison with commercially available drugs. AgO-NPs have been shown to improve the condition of gouty arthritis by reducing significantly (P ˂ 0.001) increased levels of ALT, AST, and total bilirubin. The total protein estimation results showed significant improvement at concentration of 20 µg/mL of AgO-NPs. The lipid profile results showed that high concentration (20 µg/mL) of AgO-NPs decrease the lipid content significantly as compared to control. It was concluded from this study that the antioxidant, anti-inflammatory, and antilipidemic properties of AgO-NPs may improve the hyperuricemic condition in gouty arthritis mice., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Hyperuricemia is a critical threat to human health, and conventional medical treatment only aims to treat acute gouty arthritis. Purine diet-mediated chronic hyperuricemia and related syndromes are neglected in clinical therapeutics. In this study, the prevention ability of Lacticaseibacillus rhamnosus Fmb14, screened from Chinese yogurt, was evaluated in chronic purine-induced hyperuricemia (CPH) mice. After 12 weeks of Fmb14 administration, serum uric acid (SUA) in CPH mice decreased by 36.8 %, from 179.1 to 113.2 µmol/L, and the mortality rate decreased from 30 % to 10 %. The prevention role of Fmb14 in CPH was further investigated, and the reduction of uric acid by Fmb14 was attributed to the reduction of XOD (xanthine oxidase) in the liver and URAT1 in the kidney, as well the promotion of ABCG2 in the colon. Fmb14 administration Increased ZO-1 and Occludin expression in the colon and decreased fibrosis degree in the kidney indicated that Fmb14 administration had preventive effects through the gut-kidney axis in CPH. In specific, Fmb14 administration upregulated the diversity of gut microbiota, increased short-chain fatty acids (SCFA) by 35 % in colon materials and alleviated the inflammatory response by reducing biomarkers levels of IL-1β, IL-18 and TNF-α at 11.6 %, 21.7 % and 26.5 % in serum, compared to CPH group, respectively. Additionally, 16 S rRNA sequencing showed 31.5 % upregulation of Prevotella, 20.5 % and 21.6 % downregulation of Ruminococcus and Suterella at the genus level, which may be a new gut microbial marker in hyperuricemia. In conclusion, Fmb14 ameliorated CPH through the gut-kidney axis, suggesting a new strategy to prevent hyperuricemia., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

As a popular medicinal plant traditionally used in Tibet of China, Nepeta angustifolia C. Y. Wu is mainly administered to treat apoplexia, cerebral haemorrhage, fainting and epilepsy and other symptoms, while its effect on hyperuricemia is still unclear. In the present study, we evaluated the improvement of the 70% ethanol extract of Nepeta angustifolia C. Y. Wu in fructose-induced hyperuricemic mice. The results revealed that Nepeta angustifolia C. Y. Wu significantly decreased blood glucose and blood lipid levels, as well as lowering the urinary levels of uric acid, creatinine and urea nitrogen. Meanwhile, it effectively restored the serum levels of uric acid, creatinine and urea nitrogen and inhibited serum and hepatic XOD activities and renal oxidative stress, while suppressing the secretions of TNF-α, IL-1β and IL-6 in kidney. Nepeta angustifolia C. Y. Wu also attenuated the infiltration of inflammatory cells and reduced the production and accumulation of glycogen and collagen, while restoring the dysregulated protein expressions of renal URAT1, GLUT9, OAT1 and OAT3. In summary, our results support the idea that Nepeta angustifolia C. Y. Wu is a promising agent for treating hyperuricemia.

Background: Studies have shown that hyperuricemia (HUA) is an independent risk factor for all-cause death and residual kidney function loss in peritoneal dialysis (PD) patients. The control of blood uric acid (UA) is an important link to improve the prognosis of end-stage renal disease (ESRD). As a therapeutic drug for HUA, febuxostat is rarely studied in PD patients. The purpose of our study is to investigate the safety, efficacy, and effect on residual renal function (RRF) of febuxostat in patients undergoing PD., Methods: This is a retrospective single-arm cohort study. During the study period which from September 2016 to November 2020, 191 patients underwent PD at this hospital. Among these patients, 84 were administrated for over a period of 3 months and were eventually included. These 84 patients (51 males and 33 females; average age: 55.18 years) were undergoing PD complicated with HUA or gout who received febuxostat during a regular follow-up from January 2018 to November 2020. Serum UA (sUA) levels, blood routine, liver function, and RRF were compared before and after febuxostat administration. Adverse events (AEs) resulting from febuxostat treatment were collected from medical records., Results: All 84 patients were administered febuxostat for over 3 months, including 39 for over 6 months and 26 for over 12 months. Some 60 patients were treated with febuxostat dose of 20 mg/day and the remaining 24 patients received 40 mg/day. Compared with pretreatment level, the mean sUA level was observed to be markedly reduced at 1 month after febuxostat administration (320.2±87.27 vs. 498.8±81.47 µmol/L, P<0.0001) and at 3 months (291.6±82.66 vs. 498.8±81.47 µmol/L, P<0.0001) and subsequently remained at a significantly low level for 12 months. Only 5 patients stopped febuxostat because of its associated AEs. An initial dose of 40 mg/day was associated with a higher rate of AEs compared with dose of 20 mg/day (25% vs. 18.33%, respectively). After febuxostat treatment, no significant differences were observed between RRF in the two groups., Conclusions: Febuxostat may be safe and efficient in patients undergoing PD and may not impair RRF. Febuxostat administration at dose of 20 mg/day may be an appropriate dose for patients undergoing PD.

Drug-induced hyperuricemia and gout present an increasingly prevalent problem in clinical practice. Herein, we review the urate-lowering or urate-raising effects of commonly used agents. We performed a PubMed search using the terms gout, urate, and medication, along with the specific agents/classes described herein. Reports were reviewed until 2022, and original studies were considered if they primarily or secondarily reported the effects of 1 or more drugs on serum urate level. Previous reviews were assessed for references to additional studies that described urate-altering effects of medications. Urate-changing drugs are summarized regarding their magnitude of effect, mechanism of action, and clinical significance. Potentially urate-lowering drugs include angiotensin II receptor blockers, calcium channel blockers, high-dose aspirin and salicylates, some nonsalicylate nonsteroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, sodium-glucose cotransporter 2 inhibitors, statins, and fenofibrate. Potentially urate-increasing drugs discussed include diuretics, β-blockers, insulin, pyrazinamide, ethambutol, calcineurin inhibitors, low-dose aspirin, testosterone, and lactate. In patients who have or are at risk for hyperuricemia or gout, an increased awareness of drugs that affect serum urate level may allow for prescribing that effectively treats the indicated problem while minimizing adverse effects on hyperuricemia and gout., (Copyright © 2022 Mayo Foundation for Medical Education and Research. All rights reserved.)

In recent decades, the prevalence of hyperuricemia has increased, and dietary fructose is an important risk factor for the development of this disease. This study investigated and compared the effects of Sphacelotheca reiliana polysaccharides and Phoenix dactylifera monosaccharides on a series of physiological and biochemical indicators and on the metagenomes and serum metabolites in mice with hyperuricemia caused by a high-fructose diet. S. reiliana polysaccharides inhibited uric acid biosynthesis and promoted uric acid excretion, thereby alleviating the hyperuricemia phenotype. In addition, hyperuricemia was closely related to the gut microbiota. After treatment with S. reiliana polysaccharides, the abundances of Bacteroidetes and Proteobacteria in the mouse intestines were decreased, the expression of genes involved in glycolysis/gluconeogenesis metabolic pathways and purine metabolism was downregulated, and the dysfunction of the gut microbiota was alleviated. With regard to serum metabolism, the abundance of hippuric acid, uridine, kynurenic acid, propionic acid and arachidonoyl decreased, and the abundances of serum metabolites in inflammatory pathways involved in kidney injury and gout, such as bile acid metabolism, purine metabolism and tryptophan metabolism pathways, decreased. P. dactylifera monosaccharides aggravated hyperuricemia. This research provides a valuable reference for the development of sugar applications., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Ethnopharmacology Relevance: One folk use of Alstonia scholaris (L.) R. Br. in "Dai" ethno-medicine system is to treat gouty arthritis, which might be caused by hyperuricemia, but anti-hyperuricemic investigation of A. scholaris were rarely reported., Aim of the Study: To verify anti-hyperuricemic property of A. scholaris, and explore its bioactive compounds in vivo and in vitro., Materials and Methods: The anti-hyperuricemic bioactivity of the non-alkaloids fraction and compounds were evaluated with potassium oxonate (PO) induced hyperuricemia mice model in vivo, and monosodium urate (MSU) induced human renal tubular epithelial cells (HK-2) was selected to test in vitro, respectively, with benzobromarone as the positive control. 11 triterpenoids were isolated by phytochemical methods and their structures were elucidated by spectroscopic analysis and ECD calculation., Results: The non-alkaloids fraction of A. scholaris decreased the serum uric acid (UA) level in mice model significantly at the doses of 100 mg/kg and 200 mg/kg, and then nine ursane- and two oleanane-triterpenoids including four new compounds (1-3 and 10) were isolated from the bioactive fraction, in which compounds 1, 4, 5, 6 and 10 exhibited better anti-hyperuricemic tendency in vitro by promoting the excretion of UA in MSU-induced HK-2 cell model at a concentration of 5 μM. Furthermore, compounds 1 and 4 were proved to reduce the serum UA level in mice significantly at 5 mg/kg in vivo., Conclusions: The results supported the traditional use of A. scholaris in treating gouty arthritis, and also provided new bioactive triterpenoids for further chemical and pharmacological investigation., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Purpose: Gouty arthritis is generally induced by the accumulation of monosodium urate (MSU) crystals in the joints due to elevated serum uric acid levels, potentially leading to serious pathological disorders such as nephrolithiasis, renal failure, and acute gouty arthritis. In this study, we aimed to validate the anti-gout effects of carvacrol, a phenolic monoterpene., Materials and Methods: Male Sprague-Dawley rats were divided into normal saline, disease group by injecting potassium mono-oxonate (PO) at a dose of 250 mg/kg, and three treatment groups, either with carvacrol 20 mg/kg or 50 mg/kg and 10 mg/kg allopurinol. The blood and tissue samples were subsequently collected and analyzed using different biochemical and histopathological techniques., Results: Our results revealed a significant increase in the serum levels of oxidative stress-related markers, namely, uric acid and C-reactive protein (CRP), and NLRP3 inflammasome-dependent inflammatory mediators, including nuclear factor kappa B (NF-κB) and tumor necrosis factor-alpha (TNF-α). Carvacrol administration for seven consecutive days exhibited significant anti-hyperuricemic and anti-inflammatory effects in a dose-dependent manner. Notably, the 50 mg/kg carvacrol treatment was observed to produce results similar to the allopurinol treatment. Furthermore, the renal safety of carvacrol was confirmed by the renal function test., Conclusion: Carvacrol potentially alleviates hyperuricemia-induced oxidative stress and inflammation by regulating the ROS/NRLP3/NF-κB pathway, thereby exerting protective effects against joint degeneration., Competing Interests: The authors declare no conflict of interest., (© 2022 Riaz et al.)

Iron oxide nanoparticles (FeO-NPs) exhibit exceptional properties which can be utilized in various aspects of biological sciences. In this experiment we investigated the anti-gout effectiveness of FeO-NPs in mice. BALB/c mice were induced gouty arthritis by administering monosodium urate (MSU) crystals. These gout induced mice were treated with three different concentrations of FeO-NPs (5 ppm, 10 ppm and 20 ppm). Precipitation method was utilized for the synthesis of FeO-NPs, these synthesized NPs were of average 54 nm in size and were characterized using XRD, SEM and EDS. FeO-NPs is given orally three weeks by using FeO-NPs solution to substitute drinking water. Blood biochemical parameters including liver function tests (LFTs), renal function tests (RFTs), lipid profile and blood count have been tested. It has been found that uric acid, blood urea and creatinine have decreased significantly after three weeks of FeO-NP administration (P Value < 0.001) thus suppressing hyperuricemia and gouty arthritis. Additionally, the liver enzymes analysis showed a slight increase in AST, ALT and alkaline phosphatase levels (P Value < 0.001). Histopathological research revealed no significant abnormal changes in the liver, muscle and kidney muscles of the test groups. The findings showed that FeO-NPs can be used for the successful treatment of hyperuricemic condition and gouty arthritis in the coming future in place of commercially available medicines., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

A series of 4-(phenoxymethyl)-1H-1,2,3-triazole derivatives were designed, synthesized, and evaluated for their xanthine oxidase (XO) inhibitory activities. Among these compounds, 9m emerged as the most effective XO inhibitor with an IC 50 value of 0.70 μM, which was approximately 14-fold more potent than allopurinol. Additionally, compound 9m displayed favorable drug-like properties with ligand efficiency (LE) and lipophilic ligand efficiency (LLE) values of 0.33 and 3.41, respectively. We further explored the binding mode of 9m in complex with XO by molecular docking and molecular dynamics studies. In vivo hypouricemic studies also suggested that 9m could effectively lower the serum uric acid levels of rat. In summary, compound 9m could be a promising lead for further development of XO inhibitors., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Acne vulgaris is a chronic inflammatory disease affecting the pilosebaceous unit. Systemic isotretinoin (SI) is an effective, synthetic vitamin A derivative in the treatment of resistant acne or nodulocystic acne. This study aimed to investigate uric acid levels and laboratory parameters in patients receiving isotretinoin treatment., Materials and Methods: This study included 114 patients who were under SI treatment of 0.2-0.5 mg/kg/day aged between 17 and 44 years old. We retrospectively evaluated total cholesterol, triglyceride, aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea, creatinine, creatinine kinase, uric acid, thrombocyte (Plt), and leucocyte (WBC) levels prior and on the fourth month of the treatment from the patients' records and compared these data statistically., Results: The AST, creatinine kinase, cholesterol, triglyceride, and thrombocyte levels were significantly different ( p <.001, p <.001, p <.001, p <.001, and p =.02, respectively), and no statistically significant differences were noted among the uric acid, creatinine, ALT, and WBC levels in the comparison of the baseline values and values at the fourth month of treatment ( p >.05)., Conclusions: SI treatment of 0.2-0.5 mg/kg/day did not make significant alterations on serum uric acid levels. Besides, all alterations occurred within normal ranges.

The purpose of this study was to explore the hypouricemic effect in hyperuricemia mice of triterpenoid acids from Inonotus obliquus (TAIO), and decipher of the underlying xanthine oxidase inhibitory mechanism. Measurement of xanthine oxidase (XO) inhibitory activity was assayed. Organ indexes and serum biochemical indicators were measured in potassium oxonate-induced hyperuricemia mice. Studies showed that TAIO had the strong inhibitory effect on XO activity, and its inhibition type was mixed and reversible. In vivo, TAIO decreased efficiently uric acid level, hepatic XO, serum blood urea nitrogen activities in hyperuricemia mice. Indicating that TAIO may ameliorate kidney damage and relieve inflammation in hyperuricemic mice, and had the inhibitory effect on XO activity. Furthermore, eight triterpenoids were identified by Ultra performance liquid chromatography electrospray quadrupole time of flight mass spectrometry. These findings proved that triterpenoids from Inonotus obliquus would have potential biological characteristics and effect on controlling hyperuricemia and gout as an active supplement. PRACTICAL APPLICATIONS: There are a large amount of evidence indicating that hyperuricemia and gout are related to the hypertension and obesity. And gout and hyperuricemia are also possible connection with cardiovascular disease and metabolic syndrome. Currently, xanthine oxidase is the target of many kinds of chemical drugs at present, but the therapeutic drugs used in clinical medicine will produce more or less side effects. Therefore, the aim of this study was to explore the material basis of effective substances for reducing uric acid in Inonotus obliquus and to evaluate its effect. This study can provide a promising application of Inonotus obliquus in the fields of functional foods or medicines for gout and hyperuricemia., (© 2021 Wiley Periodicals LLC.)

In vivo assays and chemical analyses were performed on the ethanolic extract from leaves of Eruca sativa . UHPLC-ESI-QTOF analysis confirmed the presence of glucosinolates and flavonol glucosides. The major flavonoid of the ethanolic extract, kaempferol-3,4'-di- O -β-glucoside, was isolated, a HPLC-DAD method developed and validated to quantify its content in the extract. In vivo experiments were carried out on Wistar rats with hyperuricaemia induced by potassium oxonate and uric acid. A hypouricaemic effect was observed in hyperuricaemic Wistar rats treated with ethanolic extract at dose of 125 mg/kg and kaempferol-3,4'-di- O -β-glucoside at dose of 10 mg/kg. The main anti-hyperuricaemic mechanism observed in the extract was uricosuric. Kaempferol-3,4'-di- O -β-glucoside was identified as an important component responsible for the total activity of the ethanolic extract and was considered as a good chemical and biological marker of the ethanolic extract of E. sativa. The obtained results indicated the potential of E. sativa in the treatment of hyperuricaemia and its comorbidities.

In the present study, the ameliorative effects of polyphenols from purple potato leaves (PSPLP) on hyperuricemia were investigated. HPLC-MS analysis showed that PSPLP was mainly composed of caffeoylquinic acid derivatives (84%). PSPLP inhibited the levels of cytokines (IL-1β, IL-6, and TNF-α) in monosodium urate-induced RAW264.7 cells. In vivo, PSPLP significantly inhibited the level of uric acid in hyperuricemia mice from 209.6 to 166.6 μM, and significantly interfered with the activities of xanthine oxidase (XOD) and adenosine deaminase in liver, the activity of XOD decreased from 13.5 to 11.6 U/gprot. PSPLP can decrease serum creatinine level from 105 to 59 μM, and urea nitrogen level from 21.9 to 14.1 mM, which can effectively protect kidney. These results provide a reference for future research and application of PSPLP as a functional food to intervene hyperuricemia and associated inflammation. PRACTICAL APPLICATIONS: This study evaluated the effect of polyphenols from purple potato leaves (PSPLP) on hyperuricemia. The results suggested that PSPLP has an important role in the intervention of hyperuricemia and hyperuricemic-related inflammation or renal injury, and can be used in the application of functional foods. These results provided a basis for further study on the biological activities of polyphenols from purple sweet potato leaves., (© 2022 Wiley Periodicals LLC.)

Heavy metals, including cadmium, are suspected to increase serum uric acid levels and hyperuricemia in both gender, but the evidences about this are inconclusive. To determine whether serum cadmium in American adults(≥19 years old) is associated with uric acid levels and risk of hyperuricemia, 2620 participants from the US National Health and Nutrition Examination Survey were recruited. Hyperuricemia was defined as a serum UA concentration ≥ 416.4 μmol/L for men and ≥ 356.9 μmol/L for women. Regression analyses were used to analyze the association of cadmium with serum UA and hyperuricemia. The threshold effect explored using two-piecewise linear regression model by the smoothing plot. The overall median of blood cadmium was 0.27 μg/L in men and 0.33μg/L in women. After adjusting for the covariates (race; age; education; BMI; smoke status; alcohol consumption; blood lead; hypertension; diabetes mellitus; hemoglobin; eGFR; triglyceride; and cholesterol), a non-linear relationship between hyperuricemia and cadmium among men was detected; and there was a positive line correlation between them for women (OR = 1.58; 95%CI (1.08, 2.31)). No significant association between uric acid and cadmium in either gender was found. Blood cadmium levels in the range currently considered acceptable were positively associated with increased prevalence of hyperuricemia in women, but inversely associated in men (cadmium <0.77μg/L)., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aims and Objectives: Fructose, as a ubiquitous monosaccharide, can promote ATP consumption and elevate circulating Uric Acid (UA) levels. Our previous studies have confirmed that the macroporous resin extract of Dendrobium officinale leaves (DoMRE) could reduce the UA level of rats with hyperuricemia induced by a high-purine diet. This study aimed to investigate whether DoMRE had a UA-lowering effect on rats with hyperuricemia caused by fructose combined with potassium oxonate, so as to further clarify the UA-lowering effect of DoMRE, and to explore the UAlowering effect of DoMRE on both UA production and excretion., Materials and Methods: Rats with hyperuricemia induced by fructose and potassium oxonate were administered with DoMRE and vehicle control, respectively, to compare the effects of the drugs. At the end of the experiment, the Serum Uric Acid (SUA) and Creatinine (Cr) levels were measured using an automatic biochemical analyzer, the activities of xanthine oxidase (XOD) were measured using an assay kit, and the protein expressions of Urate Transporter 1 (URAT1), glucose transporter 9 (GLUT9), and ATP-Binding Cassette Superfamily G member 2 (ABCG2) were assessed using immune-histochemical and western blot analyses. Hematoxylin and eosin staining was used to assess the histological changes in the kidney, liver, and intestine., Results: Fructose and potassium induced hyperuricemia in rats. Meanwhile, the activities of XOD were markedly augmented, the expression of URAT1 and GLUT9 was promoted, and the expression of ABCG2 was reduced, which were conducive to the elevation of UA. However, exposure to DoMRE reversed these fructose- and potassium oxonate-induced negative alternations in rats. The activities of XOD were recovered to the normal level, reducing UA formation; the expressions of URAT1, ABCG2, and GLUT9 returned to the normal level, resulting in an increase in renal urate excretion., Conclusion: DoMRE reduces UA levels in rats with hyperuricemia induced by fructose combined with potassium oxonate by inhibiting XOD activity and regulating the expression of ABCG2, URAT1, and GLUT9. DoMRE is a potential therapeutic agent for treating hyperuricemia through inhibiting UA formation and promoting UA excretion., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Purpose: Hyperuricemia is associated with increased cardiovascular risk. Because patients with asymptomatic hyperuricemia (AH) experience no immediate discomfort and there are possible side effects of urate-lowering drugs, treatment for AH is controversial. We aimed to perform a network meta-analysis (NMA) to investigate the effects of different urate-lowering therapies (ULTs) on serum uric acid level, renal function, blood pressure (BP), and safety in AH patients., Methods: This NMA focused on AH patients. The intervention group (patients receiving urate-lowering drugs) was compared with others using other types of drugs, placebo, or usual care. We undertook a NMA under the frequentist framework by R., Results: Thirteen eligible trials were identified. The interventions included allopurinol, febuxostat, and benzbromarone, which are not approved in the United States. Benzbromarone and allopurinol had the best efficacy on lowering serum uric acid level in short-term and long-term follow-up (mean difference [MD] = -3.05; 95% CI, -5.19 to -0.91 vs MD = -3.17; 95% CI, -5.19 to -1.15). Patients using allopurinol had significantly higher eGFR than using placebo in both short-term and long-term follow-up (MD = 3.07; 95% CI, 0.18 to 5.95 vs MD = 4.10; 95% CI, 2.66 to 5.54). No difference in BP was found between groups, except for febuxostat to diastolic BP after long-term treatment (MD = -1.47; 95% CI, -2.91 to -0.04). No statistically increased odds of safety events were found with the use of ULT., Conclusions: Our result showed that in AH patients, allopurinol has a renoprotective effect. Febuxostat has a significant impact in lowering diastolic BP. ULT does not result in a higher risk of safety events., Competing Interests: Conflict of interest: None., (© Copyright 2022 by the American Board of Family Medicine.)

Phellodendri Chinensis Cortex (PC) is a traditional medicinal material used to treat gout and hyperuricemia (HUA) in China. Berberine (BBR), the main component of PC, possesses anti-hyperuricemic and anti-gout effects. However, BBR exhibits low bioavailability due to its extensive metabolism and limited absorption. Thus, the metabolites of BBR are believed to be the potential active forms responsible for its in vivo biological activities. Berberrubine (BRB), one of the major metabolites of BBR, exhibits appreciable biological activities even superior to BBR. In this work, the anti-hyperuricemic efficacy of BRB was investigated in HUA model mice induced by co-administration with intraperitoneal potassium oxonate (PO) and oral hypoxanthine (HX) for 7 days. Results showed that administration with BRB (6.25, 12.5, and 25.0 mg/kg) significantly decreased the serum levels of uric acid (UA) by 49.70%, 75.35%, and 75.96% respectively, when compared to the HUA group. In addition, BRB sharply decreased the levels of blood urea nitrogen (BUN) (by 19.62%, 28.98%, and 38.72%, respectively) and serum creatinine (CRE) (by 16.19%, 25.07%, and 52.08%, respectively) and reversed the PO/HX-induced renal histopathological damage dose-dependently. Additionally, BRB lowered the hepatic XOD activity, downregulated the expressions of glucose transporter 9 (GLUT9) and urate transporter 1 (URAT1), upregulated expressions of organic anion transporter 1/3 (OAT1/3) and ATP-binding cassette transporter subfamily G member 2 (ABCG2) at both protein and mRNA levels, and suppressed the activation of the JAK2/STAT3 signaling pathway. In addition, BRB significantly decreased the levels of inflammatory mediators (IL-1β, IL-6, and TNF-α). In conclusion, our study indicated that BRB exerted anti-hyperuricemic effect, at least in part, via regulating the urate transporter expressions and suppressing the JAK2/STAT3 signaling pathway. BRB was believed to be promising for further development into a potential therapeutic agent for HUA treatment., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Hyperuricemia (HUA) is an important risk factor for gout, renal dysfunction and cardiovascular diseases. The whole plant of Persicaria capitata (Buch.-Ham. ex D. Don) H. Gross, namely Persicaria capitata herba, is a well-known ethnic herb with potent therapeutic effects on urinary tract infections and urinary calculus, yet previous reports have only focused on its effect on urinary tract infections., Purpose: To evaluate the therapeutic potential of P. capitata herba against gout by investigating its antihyperuricemia and antigouty arthritis effects and possible mechanisms., Methods: The ethanol extract (EP) and water extract (WP) of P. capitata herba were prepared by extracting dried and ground whole plants of P. capitata with 75% ethanol and water, respectively, followed by removal of solvents and characterization by UHPLC-Q-TOF/MS. The antihyperuricemia and antigouty arthritis effects of the two extracts were evaluated in a potassium oxonate- and hypoxanthine-induced hyperuricemia mouse model and a monosodium urate crystal (MSUC)-induced acute gouty arthritis mouse model, respectively. The mechanisms were investigated by testing their effects on the expression of correlated proteins (by Western blot) and mRNAs (by RT-PCR)., Results: UHPLC-HRMS fingerprinting and two chemical markers (i.e., quercetin and quercitrin) determination were used for the characterization of the WP and EP extracts. Both WP and EP extracts showed pronounced antihyperuricemia activities, with a remarkable decline in serum uric acid and a marked increase in urine uric acid in hyperuricemic mice. Unlike the clinical xanthine oxidase (XOD) inhibitor allopurinol, WP and EP did not show any distinct renal toxicities. The underlying antihyperuricemia mechanism involves the inhibition of the activity and expression of XOD and the downregulation of the mRNA and protein expression of glucose transporter 9 (GLUT9) and urate transporter 1 (URAT1). The extracts of P. capitata herba also demonstrated remarkable anti-inflammatory activity in MSUC-induced acute gouty arthritis mice. The mechanism might involve inhibitory effects on the expression of proinflammatory factors., Conclusions: The extracts of P. capitata herba possessed pronounced antihyperuricemia and antigouty arthritis effects and were, therefore, promising natural medicines for hyperuricemia-related disorders and gouty arthritis. The use of P. capitata herba for the treatment of urinary calculus may be, at least to some degree, related to its potential as an antihyperuricemia and antigouty arthritis drug., (Copyright © 2021. Published by Elsevier GmbH.)

Context: The uric acid metabolism pathway is more similar in primates and humans than in rodents. However, there are no reports of using primates to establish animal models of hyperuricaemia (HUA)., Objectives: To establish an animal model highly related to HUA in humans., Materials and Methods: Inosine (75, 100 and 200 mg/kg) was intraperitoneally administered to adult male rhesus monkeys ( n  = 5/group). Blood samples were collected over 8 h, and serum uric acid (SUA) level was determined using commercial assay kits. XO and PNP expression in the liver and URAT1, OAT4 and ABCG2 expression in the kidneys were examined by qPCR and Western blotting to assess the effects of inosine on purine and uric acid metabolism. The validity of the acute HUA model was assessed using ulodesine, allopurinol and febuxostat., Results: Inosine (200 mg/kg) effectively increased the SUA level in rhesus monkeys from 51.77 ± 14.48 at 0 h to 178.32 ± 14.47 μmol/L within 30 min and to peak levels (201.41 ± 42.73 μmol/L) at 1 h. PNP mRNA level was increased, whereas XO mRNA and protein levels in the liver were decreased by the inosine group compared with those in the control group. No changes in mRNA and protein levels of the renal uric acid transporter were observed. Ulodesine, allopurinol and febuxostat eliminated the inosine-induced elevation in SUA in tested monkeys., Conclusions: An acute HUA animal model with high reproducibility was induced; it can be applied to evaluate new anti-HUA drugs in vivo and explore the disease pathogenesis.

Inflammation is an important pathological feature of hyperuricemia, which in turn aggravates hyperuricemia. Astaxanthin is a carotenoid with strong antioxidant capacity and possesses many biological activities. This study was aimed to evaluate the effect of astaxanthin (ASX) on hyperuricemia and kidney inflammation in potassium oxonate (PO) and hypoxanthine (HX)-induced hyperuricemic mice. Male ICR mice were administered intragastrically with PO and HX (250 mg/kg, respectively) for 14 days. ASX was given by gavage one hour after PO and HX administration. ASX treatment significantly reversed PO and HX-induced hyperuricemia and kidney inflammation in mice as evidenced by decreased serum levels of uric acid (UA), creatinine (Cr), blood urea nitrogen (BUN), and inflammatory factors (IL-1β, IL-6, and TNF-α) and increased activities of antioxidant enzymes (CAT, SOD and GSH-Px). Furthermore, ASX administration effectively inhibited the activities of key enzymes related to UA synthesis (xanthine oxidase (XOD) and adenosine deaminase (ADA)) and modulated the protein expressions of NF-κ B p65, p-NF-κ B p65, Iκ Bα, p-Iκ Bα, NLRP3, ASC, Caspase-1, and cleavedCaspase-1 involved in inflammation pathways. Our results suggested that ASX improved hyperuricemia and kidney inflammation induced by PO and HX, probably by reducing UA synthesis and suppressing the NF-κ B and NLRP3 pathways simultaneously.

Background: Tolvaptan is a vasopressin type 2 receptor antagonist and has been used to treat autosomal dominant polycystic kidney disease (ADPKD) since 2014. There has been limited real-world data on the safety and efficacy of tolvaptan., Methods: This post-marketing surveillance was conducted to evaluate the long-term safety and the efficacy of tolvaptan in Japanese patients with ADPKD in real-world clinical settings. The baseline characteristics of 1630 patients treated with tolvaptan are reported. Safety analysis comprises evaluation of adverse drug reactions (ADRs). The efficacy evaluation includes percent change in total kidney volume (TKV) and change in estimated glomerular filtration rate (eGFR) before and after tolvaptan treatment., Results: Mean age was 49.7 ± 11.2 years and 843 (51.7%) patients were male. Baseline TKV was 2158 ± 1346 mL and eGFR was 44.4 ± 21.7 mL/min/1.73 m 2 . The majority of CKD patients were stage G3b (27.0%) and G4 (30.1%). Frequently reported ADRs were hepatic function abnormal (8.3%), thirst (8.2%), and hyperuricaemia (6.9%). The frequency of ALT elevation (> 30 and > 90 IU/L) was slightly high (32.9 and 8.3%) to previous studies. After tolvaptan treatment, the annual rate of percentage change in TKV reduced from 11.68%/year to 2.73%/year (P < 0.0001). Similar results were also obtained for the effect on change in eGFR from - 3.31 to - 2.28 mL/min/1.73 m 2 /year after initiation of tolvaptan treatment (P = 0.0403)., Conclusion: There were no major problems with safety of tolvaptan treatment and comparable efficacy for TKV and eGFR was observed in relation to the previous pivotal two randomized control trials in this post-marketing surveillance., (© 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.)

Sonneratia apetala seeds are considered as prospective nutraceuticals with a high content of unsaturated fatty acids (UFAs) which are mainly distributed in the oil. It is well-known that UFAs could exhibit urate-lowering potency and protect against renal injury, indicating that S. apetala seed oil (SSO) may possess hypouricemic and nephroprotective effects. Consequently, the present work attempted to probe into the effects and mechanisms of SSO on potassium oxonate/hypoxanthine-induced hyperuricemia and associated renal injury. The results indicated that SSO treatment prominently inhibited the increase of serum uric acid (UA), creatinine (CRE), and urea nitrogen (BUN) levels and hepatic xanthine oxidase (XOD) activity in hyperuricemia mice. Kidney indexes and histopathological lesions were also remarkably ameliorated. Additionally, SSO treatment improved the renal anti-oxidant status in hyperuricemia mice by significantly reversing the increase in ROS and MDA levels as well as the decline in SOD, CAT and GSH-Px activities. SSO dramatically downregulated the expression and secretion of pro-inflammatory factors involving MCP-1, IL-1β, IL-6, IL-18 and TNF-α elicited by hyperuricemia. Furthermore, after SSO treatment, increased protein expressions of GLUT9, URAT1 and OAT1 in the hyperuricemia mice were obviously reversed. SSO treatment enormously restored Nrf2 activation and subsequent translation of related anti-oxidative enzymes in the kidneys. TXNIP/NLRP3 inflammasome activation was also obviously suppressed by SSO. In conclusion, SSO exerted favorable hypouricemic effects owing to its dual functions of downregulating the XOD activity and modulating the expressions of renal urate transport-associated proteins, and it also could alleviate hyperuricemia-induced renal injury by restoring the Keap1-Nrf2 pathway and blocking the TXNIP/NLRP3 inflammasome activation.

Mesenchymal stem cells (MSCs), due to their multi-directional differentiation, paracrine and immunomodulation potentials, and the capacity of homing to target organ, have been reported to facilitate regeneration and repair of kidney and improve kidney function in acute or chronic kidney injury. The present study was aimed to evaluate whether MSCs could have a protective effect in hyperuricemic nephropathy (HN) and the underlying mechanisms. A rat HN model was established by oral administration of a mixture of potassium oxonate (PO, 1.5 g/kg) and adenine (Ad, 50 mg/kg) daily for 4 weeks. For MSCs treatment, MSCs (3 × 10 6 cells/kg per week) were injected via tail vein from the 2nd week for 3 times. The results showed that along with the elevated uric acid (UA) in HN rats, creatinine (CREA), blood urea nitrogen (BUN), microalbuminuria (MAU) and 24-hour urinary protein levels were significantly increased comparing with the normal control rats, while decreased after MSCs treatment. Moreover, the mRNA levels of inflammation and fibrosis-related gene were reduced in UA + MSCs group. Consistently, hematoxylin-eosin (HE) staining results showed the destruction of kidney structure and fibrosis were significantly alleviated after MSCs administration. Similarly, in vitro, NRK-52Es cells were treated with high concentration UA (10 mg/dL) in the presence of MSCs, and we found that MSCs co-culture could inhibited UA-induced cell injury, characterized as improvement of cell viability and proliferation, inhibition of apoptosis, inflammation, and fibrosis. Collectively, MSCs treatment could effectively attenuate UA-induced renal injury, and thus it might be a potential therapy to hyperuricemia-related renal diseases., (Copyright © 2021. Published by Elsevier B.V.)

Background: Hyperuricemia (HUA) is a serious public health concern globally that needs to be solved. It is closely related to gout and other metabolic diseases. To develop a safe and effective dietary supplementation for alleviating HUA, we investigated the effects of whey protein hydrolysate (WPH) on HUA and associated renal dysfunction and explored their underlying mechanism., Results: Potassium oxonate was used to induce HUA in model rats, who were then administered WPH for 21 days. The results showed that WPH significantly inhibited xanthine oxidase and adenosine deaminase activity in serum and liver, decreased uric acid (UA), creatinine, and blood urea nitrogen levels in serum, and increased the UA excretion in urine. In addition, WPH downregulated the expression of urate transporter 1 and upregulated the expression of organic anion transporter 1, adenosine triphosphate binding cassette subfamily G member 2, organic cation/carnitine transporters 1 and 2, and organic cation transporter 1 in kidneys., Conclusion: These findings demonstrated for the first time that WPH could alleviate HUA by inhibiting UA production and promoting UA excretion, and improve the renal dysfunction caused by HUA. Thus, WPH may be a potential functional ingredient for the prevention and treatment of HUA and associated renal dysfunction. © 2021 Society of Chemical Industry., (© 2021 Society of Chemical Industry.)

Objective: Observational studies have consistently demonstrated that serum urate level positively correlates with bone mineral density (BMD). We undertook this study to determine whether moderate hyperuricemia induced by inosine supplements influences bone turnover markers in postmenopausal women over a 6-month period., Methods: One hundred twenty postmenopausal women were recruited for a 6-month randomized, double-blind, placebo-controlled trial. Key exclusion criteria were osteoporosis, previous fragility fracture, bisphosphonate therapy, gout, kidney stones, and a urine pH level of ≤5.0. Participants were randomized in a 1:1 ratio to receive placebo or inosine. The coprimary end points were change in levels of N-propeptide of type I procollagen (PINP) and change in levels of β-C-telopeptide of type I collagen (β-CTX). Change in BMD, as measured by dual x-ray absorptiometry, was an exploratory end point., Results: Administration of inosine led to a significant increase in serum urate concentration over the study period (P < 0.0001 for all follow-up time points). At week 26, the mean change in serum urate concentration was +0.13 mmoles/liter (+2.2 mg/dl) in the inosine group and 0.00 mmoles/liter (0 mg/dl) in the placebo group. There was no difference in PINP or β-CTX levels between groups over the 6 months. There were no significant changes in bone density between groups over the 6 months. Adverse events and serious adverse events were similar between the 2 groups., Conclusion: This clinical trial shows that although inosine supplementation leads to sustained increases in serum urate levels over a 6-month period, it does not alter markers of bone turnover in postmenopausal women. These findings do not support the concept that urate has direct biologic effects on bone turnover., (© 2021, American College of Rheumatology.)

A series of N-arylalkanyl 2-naphthamides (Xa~e), which were predicted from virtual molecular docking on a built xanthine oxidase template as potential inhibitors, were synthesized. Their inhibitory activity against xanthine oxidase was assayed. Among these prepared, compounds Xb (IC 50 13.6 μM), Xc (IC 50 13.1 μM), and Xd (IC 50 12.5 μM) showed comparable inhibitory activity to allopurinol (IC 50 22.1 μM). The in vitro assay result correlated well with molecular docking scores, ΔG = -16.99, -17.66, and -17.13 Kcal/mol, respectively. On the potassium oxonate-induced hyperuricemic mice model, oral administration of Xc-Ac (40 mg/ Kg), the per-O-acetylated Xc, could reduce the blood uric acid level by 60% in comparison to the normal control group and is statistically significant (p < .01) while compared with the hyperuricemic mice group., (© 2021 Wiley Periodicals, LLC.)

Objectives: The effect of coffee on serum uric acid (SUA) has shown conflicting results. This study was to determine the effects of caffeinated coffee (CC) and decaffeinated coffee (DC) on SUA, serum xanthine oxidase activity (sXOA) and urine uric acid clearance (UAC)., Methods: This was a prospective randomised within-subject experimental study design of 51 healthy male participants. Each study period consisted of 3 periods, including a control, an intervention, and washout period for 1, 3 and 1 week, respectively. During the intervention period, the participants received 2, 4 or 6 gram/day of coffee, either CC or DC., Results: For DC groups, SUA significantly decreased by 6.5 (±1.1) mg/dL to 6.2 (±1.1) mg/dL during the intervention period (p=0.014). sXOA significantly increased by 0.05 (±0.07) nmol/min/mL to 0.20 (±0.38) nmol/min/mL during the intervention period (p=0.010) of CC. For UAC, there was no significant change with CC or DC. In hyperuricaemic participants, SUA significantly decreased by 7.7 (±0.7) mg/dL to 7.2 (±0.7) mg/dL during the intervention period (p=0.028) of DC. For non-hyperuricaemic, CC significantly increased SUA by 5.9 (±0.7) mg/dL to 6.2 (±0.9) mg/dL during the intervention period (p=0.008) and significantly decreased SUA to 6.0 (±0.8) mg/dL (p=0.049) during the withdrawal period. A significant increase of sXOA according with SUA in CC groups from 0.05 (±0.07) nmol/min/mL to 0.25 (±0.44) nmol/min/mL during the intervention period (p=0.040) was presented in non-hyperuricaemic participants., Conclusions: DC had a significant decrease of SUA during the intervention period. However, in non-HUS participants, SUA significantly increased in CC.

Camellia japonica bee pollen is one of the major types of bee pollen in China and exhibits antioxidant and anti-inflammatory activities. The aims of our study were to evaluate the effects and the possible mechanism of Camellia japonica bee pollen polyphenols on the treatment of hyperuricemia induced by potassium oxonate (PO). The results showed that Camellia japonica bee pollen ethyl acetate extract (CPE-E) owned abundant phenolic compounds and strong antioxidant capabilities. Administration with CPE-E for two weeks greatly reduced serum uric acid and improved renal function. It inhibited liver xanthine oxidase (XOD) activity and regulated the expression of urate transporter 1 (URAT1), glucose transporter 9 (GLUT9), organic anion transporter 1 (OAT1), organic cation transporter 1 (OCT1) and ATP-binding cassette superfamily gmember 2 (ABCG2) in kidneys. Moreover, CPE-E suppressed the activation of the toll-like receptor 4/myeloid differentiation factor 88/nuclear factor-κB (TLR4/MyD88/NF-κB) signaling pathway and nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome in PO-treated mice, and related inflammatory cytokines were reduced. CPE-E also modulated gut microbiota structure, showing that the abundance of Lactobacillus and Clostridiaceae increased in hyperuicemic mice. This study was conducted to explore the protective effect of CPE-E on hyperuricemia and provide new thoughts for the exploitation of Camellia japonica bee pollen.

Hyperuricemia contributes to chronic kidney disease development. However, it has been historically viewed with limited research interest. In this study, we mimicked the development of hyperuricemic nephropathy by using a potassium oxonate-induced hyperuricemia rat model. We found that administering vitamin C at 10 mg/kg/day effectively ameliorated hyperuricemic nephropathy. Compared to the control group, rats with hyperuricemia had significantly increased serum uric acid level, xanthine oxidase activity, and urine microalbumin level, by 5-fold, 1.5-fold, and 4-fold, respectively. At the same time, vitamin C supplementation reverted these values by 20% for serum uric acid level and xanthine oxidase activity and 50% for microalbumin level. Vitamin C also alleviated renal pathology and decreased the expression of pro-inflammatory and pro-fibrotic markers. A further mechanistic study suggested that vitamin C might attenuate hyperuricemic nephropathy in renal tubular epithelial cells induced by monosodium urate (MSU) crystal, at least in part, by directly inhibiting IL-6/JAK2/STAT3 signaling pathway. Meanwhile, in macrophages, vitamin C inhibited the expression of TGF-β, and reduced ROS level induced by MSU by about 35%. In short, our results suggest that vitamin C supplementation delay the progression of hyperuricemic nephropathy., (© 2021 Institute of Food Technologists®.)

Background: Hyperuricemia (HUA) is characterized by abnormal serum uric acid (UA) levels and demonstrated to be involved in renal injury leading to hyperuricemic nephropathy (HN). Apigenin (API), a flavonoid naturally present in tea, berries, fruits, and vegetables, exhibits various biological functions, such as antioxidant and anti-inflammatory activity., Purpose: To investigate the effect of API treatment in HN and to reveal its underlying mechanisms., Methods: The mice with HN were induced by potassium oxonate intraperitoneally and orally administered for two weeks. The effects of API on renal function, inflammation, fibrosis, and uric acid (UA) metabolism in mice with HN were evaluated. The effects of API on urate transporters were further examined in vitro., Results: The mice with HN exhibited abnormal renal urate excretion and renal dysfunction accompanied by increased renal inflammation and fibrosis. In contrast, API reduced the levels of serum UA, serum creatinine (CRE), blood urea nitrogen (BUN) and renal inflammatory factors in mice with HN. Besides, API ameliorated the renal fibrosis via Wnt/β-catenin pathway suppression. Furthermore, API potently promoted urinary UA excretion and inhibited renal urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) in mice with HN. In vitro, API competitively inhibited URAT1 and GLUT9 in a dose-dependent manner, with IC 50 values of 0.64 ± 0.14 μM and 2.63 ± 0.69 μM, respectively., Conclusions: API could effectively attenuate HN through co-inhibiting UA reabsorption and Wnt/β-catenin pathway, and thus it might be a potential therapy to HN., (Copyright © 2021 Elsevier GmbH. All rights reserved.)

Gout is a multifaceted inflammatory disease involving vascular impairments induced by hyperuricemia. Experiments using human umbilical vein endothelial cells treated with uric acid (UA), monosodium urate (MSU), or serum from gout patients showed increased expression of pro-inflammatory genes (ie, VCAM1, ICAM1, CYR61, CCNA1, and E2F1) with attendant increase in monocyte adhesion. Mechanistically, UA- or MSU-induced SREBP2 expression and its transcriptional activity. RNA sequencing analysis and real-time PCR showed the induction of YAP signaling and pro-inflammatory pathways in HUVECs transfected with adenovirus-SREBP2. The SREBP2 knockdown by siRNA partially abolished UA- or MSU-induced YAP activity, pro-inflammatory gene expression, and monocytes adhesion. Vascular intima from transgenic mice overexpressing SREBP2 in endothelium or mice with hyperuricemia exhibited activated YAP signaling and increased expression of pro-inflammatory genes. Betulin, an SREBP pharmacological inhibitor, attenuated the UA-, MSU-, or gout serum-induced endothelial cell inflammation and dysfunction. In the human study, endothelial cell function, assessed by EndoPAT, was negatively correlated with serum UA level among gouty patients and healthy controls. Collectively, UA or MSU causes endothelial dysfunction via SREBP2 transactivation of YAP. Betulin inhibition of SREBP2 may restrain gout-induced endothelial dysfunction., (© 2021 Federation of American Societies for Experimental Biology.)

Lobetyolin (LBT), a general marker compound mainly found in Codonopsis plants including C. pilosula , C. tubulosa , and C. lanceolata , exhibits antitumor, antiviral, anti-inflammatory, mucosal protective, and antioxidant activities. Xanthine oxidase (XO) catalyzes the formation of uric acid from xanthine, a critical metabolic pathway related to hyperuricemia and gout. The aim of this study was to investigate the effect of LBT on XO activity and its mechanism using in vitro enzyme assay system and in vivo potassium oxonate-induced hyperuricemic mice. LBT was found to weakly inhibit XO activity via a mixed type mechanism. Consistently, the impact of 1-week oral LBT treatment on serum XO activity in vivo is limited in hyperuricemic mice. However, oral LBT at 50 mg/kg significantly reduced hepatic XO activity in vivo . To the best of our knowledge, this is the first study to report effects of LBT on XO activity and its inhibition mechanism.

Ethnopharmacological Relevance: Moringa oleifera Lam. leaf (MOL), a rich source of protein and phenolics, was traditionally used to treat various diseases including headaches, fevers, sore throat and dyslipidemia. Recently, MOL was reported to possess antioxidant, anti-dyslipidemia and hepato-renal protective activities, indicating that MOL could become a potential agent to improve metabolic disorders associated with hyperuricemia. The antihyperuricemic effect of MOL hydrolysate (MOLH) with high contents of phenolics and peptides remains unknown., Aim of the Study: The aim of this study is to investigate xanthine oxidase (XO) inhibitory activity of MOLH, to clarify phenolic and peptide profiles of MOLH, and to evaluate possible mechanism underlying the antihyperuricemic effect of MOLH., Materials and Methods: MOLH was prepared by enzymatic hydrolysis using commercial trypsin. XO inhibitory activity was determined by XO reaction-UPLC-MS coupling method. The chemical profiles of the phenolic and peptide fractions of MOLH were determined by UPLC-QTOF-MS/MS. The antihyperuricemic effect of MOLH was evaluated in a potassium oxonate-induced hyperuricemic rat model at doses of 200 and 500 mg/kg. Serum uric acid (UA), urea nitrogen, creatinine (CRE), triglyceride (TG), total cholesterol, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol levels, serum XO activity, liver malondialdehyde (MDA) equivalent level, renal tumor necrosis factor-α and interleukin-1β levels, and protein expression of renal urate-anion transporter 1, glucose transporter 9 and ATP-binding cassette transporter G2 were determined., Results: The phenolic and peptide fractions played key roles in inhibiting XO activity and blocking uric acid production. Five flavonoids and sixteen polypeptides were identified in the phenolic and peptide fractions of MOLH, respectively. MOLH (200 and 500 mg/kg) could effectively reduce the serum UA level of hyperuricemic rats (p < 0.001) by regulation of serum XO activity (p < 0.05 at 200 mg/kg, p < 0.01 at 500 mg/kg) and renal urate transporters. Besides, MOLH could improve metabolic disorders associated with hyperuricemia by its multiple actions on liver MDA (p < 0.001), serum CRE (p < 0.05 at 500 mg/kg) and serum TG (p < 0.001)., Conclusion: The results provided scientific evidence that MOLH rich in phenolics and peptides ameliorated hyperuricemia and metabolic disorders. This study validated the potential use of MOLH for regulation of hyperuricemia., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose: To report a case of ribavirin-associated severe hyperuricemia in an immunocompromised patient treated for respiratory syncytial virus (RSV) infection., Summary: A 21-year-old male with a past medical history of B-cell acute lymphoblastic leukemia was in full remission after allogenic bone marrow transplantation complicated with chronic graft-versus-host disease. He was hospitalized due to fever, malaise, and respiratory symptoms. A diagnosis of RSV upper respiratory tract infection complicated by secondary pneumonia was made, and oral ribavirin (600 mg in 3 divided doses daily) and intravenous levofloxacin (750 mg once daily) were initiated. On day 2 of the hospital admission, the patient's uric acid levels had increased from a baseline of 4 to 6 mg/dL to 19.3 and 22.2 mg/dL after the fourth and fifth doses of ribavirin, respectively, and his serum creatinine steadily had increased from a baseline of 0.7 to 0.8 mg/dL to 1.6 mg/dL. Ribavirin was discontinued after the sixth dose, and a single dose of intravenous rasburicase (7.5 mg) was administered. On day 3, the patient's serum uric and creatinine concentrations had decreased to 4.7 mg/dL and 1.1 mg/dL, respectively. He continued to recover on antibiotics and was discharged with normal uric acid and serum creatinine levels., Conclusion: We report a case of severe hyperuricemia and acute kidney injury that developed early after initiation of ribavirin for RSV infection and suspected bacterial pneumonia in an immunocompromised patient without hepatitis C, requiring ribavirin discontinuation and rasburicase administration. To our knowledge, this is the first reported case of severe hyperuricemia in a patient treated with ribavirin for RSV infection rather than chronic hepatitis C. Clinicians should be aware of the possibility of acute and severe hyperuricemia following ribavirin administration., (© American Society of Health-System Pharmacists 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aim: Hyperuricemia is defined by the European Rheumatology Society as a uric acid level greater than 6 mg/dl (60 mg/l or 360 μmol/l). Our goal was to evaluate the hypouricemic effect of nettle. For this reason, we have first of all try to create an hyperuricemic animal model which is very suitable because at the level of literature there is not an exact model, there are many models and our objective is to set an adequate model., Materials and Methods: An attempt has been made to test acute and chronic hyperuricemia by varying the duration and method of induction of potassium oxonate. Similarly, attempts have been made to induce chronic hyperuricemia through an animal and vegetable diet. The reversibility of hyperuricemia was tested with a maintenance protocol., Key Findings: For the creation of the hyperuricemia model, it has been shown that acute hyperuricemia cannot be induced by short administration of potassium oxonate and persistent chronic hyperuricemia can be induced only after daily administration of oxonate of potassium by intraperitoneal injection for 15 days. Indeed, hyperuricemia was reversible after stopping the administration of potassium oxonate. The high-purine diet is also capable of inducing chronic hyperuricemia but to a less extent., Significance: After creating an adequate model of hyperuricemia while setting the dose of potassium oxonate, route of administration and duration. A maintenance protocol was followed which subsequently made it possible to deduce that the daily administration of potassium oxonate must be continued to maintain the hyperuricemia., (Copyright © 2020. Published by Elsevier Inc.)

Objective: Although the relationship between hyperuricemia and cardiovascular events has been extensively examined, data on the role of diuretic-related hyperuricemia are still scanty. The present study was designed to collect information on the relationship between diuretic-related hyperuricemia and cardiovascular events., Methods: The URic acid Right for heArt Health (URRAH) study is a nationwide, multicentre, observational cohort study involving data on individuals recruited from all the Italy territory under the patronage of the Italian Society of Hypertension with an average follow-up period of 122.3 ± 66.9 months. Patients were classified into four groups according to the diuretic use (yes vs. no) and serum uric acid (SUA) levels (higher vs. lower than the median value of 4.8 mg/dl). All-cause death, cardiovascular deaths and first cardiovascular event were considered as outcomes., Results: Seventeen thousand, seven hundred and forty-seven individuals were included in the analysis. Mean age was 57.1 ± 15.2 years, men were 45.3% and SBP and DBP amounted to 144.1 ± 24.6 and 85.2 ± 13.2 mmHg. 17.2% of individuals take diuretics of whom 58% had SUA higher than median value. Patients with hyperuricemia without diuretic use served as reference group. In multivariate adjusted analysis (sex, age, SBP, BMI, glucose, total cholesterol, and glomerular filtration rate) individuals with hyperuricemia and diuretic use exhibit a similar risk for the three outcomes as compared with the reference group., Conclusion: Our study showed that diuretic-related hyperuricemia carry a similar risk of cardiovascular events and all-cause mortality when compared with individuals that present hyperuricemia in absence of diuretic therapy., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Exposure to excessive fluoride has been associated with a number of adverse health outcomes; however, there is a lack of evidence on the relation between fluoride exposure and serum uric acid levels, especially in human populations. The present study examined a potential relationship between fluoride exposure, measured as both plasma and water fluoride concentrations, and uric acid levels in an adolescent population. A nationally representative subsample of 1933 adolescents, aged 12-19 years, in the 2013-2016 National Health and Nutrition Examination Survey was analyzed for the association of fluoride concentrations with serum uric acid levels using multivariate general linear and logistic regression models, adjusting for potential confounders. Since uric acid levels change during development, hyperuricemia was defined in this study as over the mean plus one standard deviation for each sex and age group of adolescents. Of the study participants, 276 adolescents (weighted prevalence, 16.56%) had hyperuricemia. A significant and dose-dependent increase in prevalence of hyperuricemia was seen among the participants cross increasing quartiles of plasma fluoride (p-trend = 0.0017). After adjusting for potential confounders, we found that adolescents in the higher quartiles of plasma fluoride (≥0.32 µmol/L) and in the highest quartile of water fluoride (≥0.73 mg/L) had significantly increased odds of hyperuricemia compared with those in the lowest quartile. A 1.95-fold increased odds (95% CI: 1.37, 2.77) of hyperuricemia was also observed when analyzing plasma fluoride concentrations as continuous variable. A general linear model revealed that a 1 µmol/L increase in ln-plasma fluoride was associated with a 0.212 mg/dL (p < 0.0001) increased serum uric acid level. Furthermore, a positive relationship was observed between water and plasma fluoride concentrations (β = 0.1907; p < 0.0001). Our study demonstrates a potential relation between fluoride exposure and hyperuricemia in adolescents. Further studies are warranted to overcome the limitations of this study to examine the impact of long-term exposure to low levels of fluoride during development on hyperuricemia and its related health outcomes., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Hyperuricemia is a well-known key risk factor for gout and can cause a variety of metabolic diseases. Several studies have shown that dioscin could improve metabolic symptoms and reduce the uric acid level in blood. However, there is no comprehensive metabolomic study on the anti-hyperuricemia effects of dioscin. A total of 29 adult male Kunming mice were divided into three groups: Normal (blank), PO (potassium oxonate-administrated, 200 mg/kg/day), and Dioscin (potassium oxonate + dioscin, potassium oxonate 200 mg/kg/day, dioscin 50 mg/kg/day). All mice were treated for 42 days via oral gavage. This paper implemented an untargeted metabolomics study based on 1 H NMR and LC-MS to discover the comprehensive mechanism of dioscin. Furthermore, a targeted lipidomics was fulfilled to further analyze the lipid metabolism disorder. Finally, the metabolic pathway mediated by dioscin was verified at the gene level by means of transcriptomics. The results show 53 different metabolites were closely related to the improvement of dioscin in PO-induced hyperuricemia, and 19 of them were lipids. These metabolites are mainly involved in the tricarboxylic acid cycle, lipid metabolism, amino acid metabolism, and pyrimidine metabolism. According to the transcriptomics study, the levels of 89 genes were significantly changed in the PO group compared to the normal control. Among them, six gene levels were restored by the treatment of dioscin. The six changed genes (tx1b, Tsku, Tmem163, Psmc3ip, Tcap, Tbx15) are mainly involved in the cell cycle and energy metabolism. These metabolites and genes might provide useful information for further study of the therapeutic mechanism of dioscin.

Background: Insufficient renal urate excretion and/or overproduction of uric acid (UA) are the dominant causes of hyperuricemia. Baicalein (BAL) is widely distributed in dietary plants and has extensive biological activities, including antioxidative, anti-inflammatory and antihypertensive activities., Purpose: To investigate the anti-hyperuricemic effects of BAL and the underlying mechanisms in vitro and in vivo., Methods: We investigated the inhibitory effects of BAL on GLUT9 and URAT1 in vitro through electrophysiological experiments and 14 C-urate uptake assays. To evaluate the impact of BAL on serum and urine UA, the expression of GLUT9 and URAT1, and the activity of xanthine oxidase (XOD), we developed a mouse hyperuricemia model by potassium oxonate (PO) injection. Molecular docking analysis based on homology modeling was performed to explain the predominant efficacy of BAL compared with the other test compounds., Results: BAL dose-dependently inhibited GLUT9 and URAT1 in a noncompetitive manner with IC 50 values of 30.17 ± 8.68 μM and 31.56 ± 1.37 μM, respectively. BAL (200 mg/kg) significantly decreased serum UA and enhanced renal urate excretion in PO-induced hyperuricemic mice. Moreover, the expression of GLUT9 and URAT1 in the kidney was downregulated, and XOD activity in the serum and liver was suppressed. The docking analysis revealed that BAL potently interacted with Trp336, Asp462, Tyr71 and Gln328 of GLUT9 and Ser35 and Phe241 of URAT1., Conclusion: These results indicated that BAL exerts potent antihyperuricemic efects through renal UA excretal promotion and serum UA production. Thus, we propose that BAL may be a promising treatment for the prevention of hyperuricemia owing to its multitargeted inhibitory activity., (Copyright © 2020 Elsevier GmbH. All rights reserved.)