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Recent groundbreaking advances in the structural biology of the glucose transporter 9 (GLUT9) and urate transporter 1 (URAT1) have provided critical insights into the molecular mechanisms underlying urate recognition and transport. Using cryo-electron microscopy (cryo-EM), researchers have elucidated the structures of these transporters at high resolution, thus revealing their substrate preferences and interactions with inhibitors. Several studies have highlighted the potential of specific inhibitors, such as apigenin for GLUT9, and have demonstrated the role of chloride-mediated inhibition in URAT1 function. These findings provide an excellent starting point for developing targeted therapies for hyperuricemia and gout, to enable the design of more effective and selective drugs in the future.

Context: As of today, the knowledge of the role of nutraceuticals in treating metabolic diseases such as hyperuricemia is still limited. Aims: To evaluate the mechanisms of anti-hyperuricemic and anti-gouty activity of Limonia acidissima in silico and in vivo. Methods: L. acidissima fruits fine powder was macerated simultaneously using n-hexane, ethyl acetate, ethanol, and methanol sequentially. The structures of the GC-MS-identified phytocompounds were evaluated for their pharmacokinetic properties (SwissADME), traced for receptor targets (SEA Target), and converted to 3D structures and molecular anchoring (MOE software). Networking relationship analyses were performed using Cytoscape version 3.8.2. Anti-hyperuricemia effect was assessed with hyperuricemia rats induced by potassium oxonate. The anti-inflammatory effect was evaluated on acute gouty arthritis induced by monosodium urate (MSU) crystal. Results: The predominant fatty acid contents (oleic acid, palmitoleic acid, and n-hexadecanoic acid) have satisfactory pharmacokinetic properties based on Lipinsky’s rules. PPAR-γ, FABP3, OAT1, and OAT3 were revealed as targets for the fatty acid receptors. The highest interaction was obtained from oleic acid interaction with PPAR-γ (-12.54 kcal/mol) and FABP3(-13.09 kcal/mol). The EEL 400 mg/kg effectively upregulated the protein levels of OAT1 (p=0.001) and OAT3 (p=0.048) in the kidneys of hyperuricemic rats. Moreover, EEL 400 mg/kg alleviated the swelling (p

Gout is a metabolic disease that seriously affects people's health. Polydatin, a stilbene compound isolated from Polygonum cuspidatum, has attracted much attention because of its rich biological activity and high safety. This study aimed to investigate the therapeutic effect and mechanism of polydatin on hyperuricemia (HUA) combined with gouty arthritis (GA). The results showed that polydatin reduced the levels of uric acid and inflammatory cytokines, indicating that polydatin had the effect of reducing uric acid and anti-GA. Then the inhibitors of ABCG2, NLRP3 inflammasome and NF-κB pathway (Ko143, MCC950 and QNZ) were used to demonstrate that polydatin played a role in reducing uric acid and anti-GA via regulating urate transporters, NLRP3 inflammasome and NF-κB pathway. Taken together, these results provided evidence that polydatin might be used as a potential functional ingredient for the synchronous treatment of HUA and GA.

Abstract Background Alpha-mangostin (AM) has been shown to have hypoglycemic activity. This study aimed to analyze the effects of AM at a dose of 100 mg/kg and 200 mg/kg to alleviate hyperuricemia and renal dysfunction on high-fat/high-glucose diet and low dose streptozotocin (HF/HG/STZ) injection-induced IR rat model. IR was induced in male Wistar rats by giving a HF/HG diet for 11 weeks and single injection of STZ (35 mg/kg, i.p.), then divided randomly into IR rats, IR rats treated with AM 100 and 200 mg/kgBW given by gavage for 8 weeks. At the end of the 11th week, all rats were killed, and the kidneys were taken to be analyzed for urate transporters 1 (URAT1) and glucose transporters 9 (GLUT9). We also assessed serum uric acid, proteinuria, BUN, creatinine clearance, HOMA-IR, and fasting blood glucose (FBG). Results We have found the significant increase in HOMA-IR and FBG levels of the IR rats, in comparison with its control groups, which were decreased significantly after AM administration at both doses. URAT1 and GLUT9 mRNA and protein expressions in kidney in the IR + AM at both doses groups also decreased compared those in the IR without treatment group, though the decrease in GLUT9 did not appear to be statistically significant. Consequently, hyperuricemia and renal dysfunction were attenuated by AM treatment at both doses. Conclusion After considering all findings, AM might be a potential candidate to ameliorate IR-induced hyperuricemia and renal dysfunction at least in part by modulating the renal URAT1.

Objective We aimed to observe the effect of lowering urate level of Qinglishire ( clearing heat and promoting diuresis) Prescription (QLSR) (glabrous greenbrier rhizome, plantain seed, Indian bread, chicory, kudzuvine root, and medical cyathula root) in rats with hyperuricemia with syndrome of internal retention of damp-heat. Methods The rat model of hyperuricemia was established by feeding rats with high-fat and high-sugar diet and administering potassium oxonate and oil or alcohol every other day. Sprague-Dawley rats were divided into six groups: the normal group, the model group, the Simiao Pill group (1. 2 g / kg), and the QLSR low-, medium-, and high- dose groups (1. 25, 2. 5, and 5. 0 g / kg, respectively). We observed the general state of rats. Serum uric acid (UA), urea nitrogen ( BUN), creatinine(Scr), IL-2, IL-4, IgG, IgM, NO, endothelin-1(ET-1), thromboxane(TX)-B2, and 6-ketoPGF1α levels and hepatic Na + -K + -ATPase levels were determined. The protein expression levels of ATP-binding cassette sub-family G member 2 (ABCG2) and urate transporter 1 (URAT1) in kidney tissuewere determined by Western blotting analysis; the mRNA expression levels of ABCG2, URAT1, and glucose transporter 9 (GLUT9) in rat kidney tissue were detected by PCR; and the protein contents of AQP3 and AQP4 in gastric tissuewere detected by immunohistochemistry. Results (ⅰ) Compared with the model group, QLSR low-, medium-, high- dose and Simiao Pill decreased serum UA, ET-1, TX-B2, IL-4 and gastric AQP4 (P < 0. 01, P < 0. 05), and increased hepatic Na + -K + -ATPase ( P < 0. 01). Serum NO was increase in QLSR high-dose group ( P < 0. 01) and serum 6-keto-PGF1α was increased in QLSR medium-dose group (P<0. 01). Gastric AQP3 were increased in QLSR medium- and high- dose groups(P<0. 05). Serum IgG were decreased in all QLSR groups (P<0. 01,P<0. 05), while serum IgM were decreased in QLSR medium-, high- dose and Simiao Pill group (P<0. 01, P<0. 05). (ⅱ) Simiao Pill and QLSR medium- and high- dose downregulated URAT1 mRNA expressions (P< 0. 01, P<0. 05). QLSR low-, medium-, high- dose and Simiao Pill all downregulated expressions of LUT9 mRNA ( P < 0. 05, P < 0. 01), upregulated expressions of ABCG2 mRNA ( P < 0. 01 ), and downregulated URAT1 protein expression(P<0. 05, P<0. 01). Conclusion Qinlishire Prescription had the effects of lowering blood uric acid levels. The mechanism was related to the downregulation of URAT1 gene and protein expressions, the upregulation of ABCG2 gene and protein levels, and the downregulation of GLUT9 gene expression. [ABSTRACT FROM AUTHOR]

The present study aimed to determine the effects of polysaccharides-riched Prunus mume fruit juice concentrate (PFC) on uric acid (UA) excretion and the gut microbiota in mice with chronic kidney disease (CKD). C57BL/6 mice were randomly allocated to four groups: two that were fed AIN93M diet, one of which was administered 500 mg/kg PFC, and two that were fed AIN93M diet containing 0.2% adenine, one of which was administered 500 mg/kg PFC. PFC promoted UA excretion, which may have been mediated through increases in the protein expression of ATP-binding cassette transporter G2 (ABCG2), organic anion transporter 1 (OAT1), organic carnitine transporter 2 (OCTN2), and reductions in the protein expression of glucose transporter 9 (GLUT9) and urate transporter 1 (URAT1) in kidneys of CKD mice. ABCG2 expression in the intestine was also increased by PFC administration. Additionally, PFC significantly increased large intestinal short-chain fatty acids (SCFAs) concentrations, and the number of gut microbial species, and reduced the abundance of the genera Bacteroides, Pseudoflavonifractor, Helicobacter, Clostridium_IV and Allobaculum, which have a negative effect on UA excretion. In conclusion, PFC may promote UA excretion in CKD mice by altering the expression of urate transporters and regulating the gut microbiota.

Hyperuricemia is the result of increased production and/or underexcretion of uric acid. Hyperuricemia has been epidemiologically associated with multiple comorbidities, including metabolic syndrome, gout with long-term systemic inflammation, chronic kidney disease, urolithiasis, cardiovascular disease, hypertension, rheumatoid arthritis, dyslipidemia, diabetes/insulin resistance and increased oxidative stress. Dysregulation of xanthine oxidoreductase (XOD), the enzyme that catalyzes uric acid biosynthesis primarily in the liver, and urate transporters that reabsorb urate in the renal proximal tubules (URAT1, GLUT9, OAT4 and OAT10) and secrete urate (ABCG2, OAT1, OAT3, NPT1, and NPT4) in the renal tubules and intestine, is a major cause of hyperuricemia, along with variations in the genes encoding these proteins. The first-line therapeutic drugs used to lower serum uric acid levels include XOD inhibitors that limit uric acid biosynthesis and uricosurics that decrease urate reabsorption in the renal proximal tubules and increase urate excretion into the urine and intestine via urate transporters. However, long-term use of high doses of these drugs induces acute kidney disease, chronic kidney disease and liver toxicity. Therefore, there is an urgent need for new nephroprotective drugs with improved safety profiles and tolerance. The current systematic review summarizes the characteristics of major urate transporters, the mechanisms underlying the pathogenesis of hyperuricemia, and the regulation of uric acid biosynthesis and transport. Most importantly, this review highlights the potential mechanisms of action of some naturally occurring bioactive compounds with antihyperuricemic and nephroprotective potential isolated from various medicinal plants. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Simiao Pills, a classical traditional Chinese medicine prescription recorded in Cheng Fang Bian Du , has been traditionally used to treat hyperuricemia due to its heat-clearing and diuretic properties. Studies have shown that Simiao Pills effectively reduce uric acid levels. However, further research is needed to elucidate the precise composition of Simiao Pills for treating hyperuricemia and their potential pharmacological mechanism. This study aimed to investigate the therapeutic effects of Simiao Pills on hyperuricemia, with a particular focus on evaluating their protective role against hyperuricemia-induced renal injury and elucidating the underlying mechanism of action. UPLC-MS/MS was used to identify the components of Simiao Pills. The hyperuricemia model mice were established by intraperitoneal injecting potassium oxonate (PO) and oral administrating hypoxanthine (HX). Network pharmacology, transcriptome, and metabolomics analyses were integrated to explore the mechanism of Simiao Pills in reducing uric acid and protecting the kidney. Mechanistic and functional studies were conducted to validate the potential mechanisms. Simiao Pills were found to contain 12 characteristic components. Treatment with Simiao Pills significantly reduced serum uric acid levels and ameliorated hyperuricemia-induced renal injury. Simiao Pills inhibited the enzymatic activities of XOD and XDH, and regulated the uric acid transporters in the kidney and ileum. Transcriptome and network pharmacology analyses highlighted quercetin, berberine, kaempferol, and baicalein as the principal active components of Simiao Pills acting on the kidney during hyperuricemia treatment, primarily impacting fibrosis, apoptosis, and inflammation-related signaling pathways. Metabolomic analysis unveiled 21 differential metabolites and 5 metabolic pathways associated with Simiao Pills against renal injury associated with hyperuricemia. Further experimental results validated that Simiao Pills reduced renal fibrosis, apoptotic renal cells, serum inflammation levels, and inhibited the NF-κB/NLRP3/IL-1β signaling pathway. This study demonstrated that Simiao Pills significantly reduced serum uric acid levels and improved renal injury by regulating inflammation, apoptosis, and renal fibrosis. These findings have provided a robust scientific pharmacological basis for the use of Simiao Pills in treating hyperuricemia patients. Simiao Pills alleviates renal injury associated with hyperuricemia: A multi-omics analysis. [Display omitted] [ABSTRACT FROM AUTHOR]

Hyperuricemia is a metabolic disease caused by excessive production of uric acid (UA), which can cause gout, hypertension, hyperlipidemia and other diseases. This study aimed to explore the effect of genistein on hyperuricemia and renal protection in hyperuricemic mice induced by potassium oxonate. Furthermore, genistein significantly downregulated the xanthine oxidase (XOD), adenosine deaminase levels, renal gene expressions of glucose transporter type 9 (mGLUT9) and uric acid transporter 1 (mURAT1) and upregulated organic anion transporters (mOAT1 and mOAT3) and organic cation transporters (mOCT1 and mOCT2). Additionally, genistein improved renal function, renal histopathological features and antioxidant activities in hyperuricemic mice. Genistein also attenuated renal fibrosis by suppressing the JAK2/STAT3 and Wnt/β-catenin signalling pathways in hyperuricemic mice. Overall, this study suggested that both doses of genistein have strong potential against hyperuricemia and associated disorders and may be used as natural supplements for the treatment of UA-related disorders.

Hyperuricemia is a metabolic disease caused by excessive production of uric acid (UA), which can cause gout, hypertension, hyperlipidemia and other diseases. This study aimed to explore the effect of genistein on hyperuricemia and renal protection in hyperuricemic mice induced by potassium oxonate. Furthermore, genistein significantly downregulated the xanthine oxidase (XOD), adenosine deaminase levels, renal gene expressions of glucose transporter type 9 (mGLUT9) and uric acid transporter 1 (mURAT1) and upregulated organic anion transporters (mOAT1 and mOAT3) and organic cation transporters (mOCT1 and mOCT2). Additionally, genistein improved renal function, renal histopathological features and antioxidant activities in hyperuricemic mice. Genistein also attenuated renal fibrosis by suppressing the JAK2/STAT3 and Wnt/β-catenin signalling pathways in hyperuricemic mice. Overall, this study suggested that both doses of genistein have strong potential against hyperuricemia and associated disorders and may be used as natural supplements for the treatment of UA-related disorders. [ABSTRACT FROM AUTHOR]

It is known that sunflower (Helianthus annuus L.) calathide enzymatically hydrolyzed extract (SCHE) contributes to the regulation of serum uric acid (UA); however, evidence regarding its bioactive components and mechanism are lacking. We identified two water-soluble components (scopoletin and chlorogenic acid) that are abundant in sunflower calathide, especially evaluated for the inhibition of xanthine oxidase (XO) and the expression levels of urate transporters with SCHE. Molecular docking of a chlorogenic acid–XO complex was more stable than that of the Scopoletin–XO, and its binding pockets, which closed the Mo = S center, was similar to xanthine pockets. Moreover, chlorogenic acid exhibited stronger inhibition than that of the scopoletin below 260 μ M , despite the IC50 of scopoletin (577.7 μ M ) being lower than that chlorogenic acid (844.7 μ M ) on the UA generation assessed by a spectrophotometer in vitro. It revealed that chlorogenic acid and scopoletin were competitive inhibitors of XO. In addition, the SCHE (300 μ g/mL) and chlorogenic acid (0.75 mM) obviously inhibited urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) expression levels, while scopoletin significantly upregulated the expression of GLUT9. To summarize, chlorogenic acid served a crucial role in UA regulation consistent with the SCHE and functioned as an important ingredient of SCHE. The strategic analysis of SCHE combined with scopoletin and chlorogenic acid may contribute to the development of food supplemental alternatives on UA metabolism and the reduction of agricultural byproduct waste. [ABSTRACT FROM AUTHOR]

Phellinus igniarius is an important medicinal and edible fungus with diverse biological activities. This study aimed to investigate the effects of aqueous extract from P. igniarius (API) on the treatment of hyperuricemia (HUA) and related kidney damage. The chemical constituents of API were determined. The therapeutic effects of API on HUA and renal injury were assessed in adenine/potassium oxonate (PO)-treated mice. The constituent analysis of API revealed a predominance of polysaccharides (33.4 %), followed by total flavonoids (9.1 %), and total triterpenoids (3.5 %). Compared to control, the adenine/PO treatment greatly elevated serum uric acid (UA) levels but this elevation was attenuated by API. In the liver, the expression and activity of xanthine oxidase (XOD) were increased by HUA which were diminished by API. Furthermore, API was found to enhance the expression of UA transporter ABCG2 in the kidney and intestine of HUA mice, suggesting elevating UA excretion. Additionally, API ameliorated HUA-induced renal injury, as indicated by reduced serum BUN/creatinine levels, decreased glomerular and tubular damage, and lowered fibrotic levels. Network pharmacology analysis predicted that P. igniarius may regulate mitochondrial function to improve HUA-related renal injury. This prediction was then substantialized by the API-induced upregulation of NAD+/NADH ratio, ATP level, SOD2 activity, and expression of SOD2/PCG-1α/PPARγ in the kidney of HUA mice. Our results demonstrate that API may effectively ameliorate HUA by reducing UA production in the liver and enhancing UA excretion in the kidney and intestine, and it might be a potential therapy to HUA-related renal injury. [Display omitted] • Aqueous extract of Phellinus igniarius (API) mainly contains total polysaccharides, total flavonoids and total triterpenoids. • API effectively ameliorated hyperuricemia (HUA) by reducing uric acid productionand enhancing UA excretion. • API attenuated HUA-related renal injury by improving the mitochondrial function. [ABSTRACT FROM AUTHOR]

Hyperuricemia (HUA) is caused by increased synthesis and/or insufficient excretion of uric acid (UA). Long-lasting HUA may lead to a number of diseases including gout and kidney injury. Harpagoside (Harp) is a bioactive compound with potent anti-inflammatory activity from the roots of Scrophularia ningpoensis. Nevertheless, its potential effect on HUA was not reported. The anti-HUA and nephroprotective effects of Harp on HUA mice were assessed by biochemical and histological analysis. The proteins responsible for UA production and transportation were investigated to figure out its anti-HUA mechanism, while proteins related to NF-κB/NLRP3 pathway were evaluated to reveal its nephroprotective mechanism. The safety was evaluated by testing its effect on body weight and organ coefficients. The results showed that Harp significantly reduced the SUA level and protected the kidney against HUA-induced injury but had no negative effect on safety. Mechanistically, Harp significantly reduced UA production by acting as inhibitors of xanthine oxidase (XOD) and adenosine deaminase (ADA) and decreased UA excretion by acting as activators of ABCG2, OAT1 and inhibitors of GLUT9 and URAT1. Moreover, Harp markedly reduced infiltration of inflammatory cells and down-regulated expressions of TNF-α, NF-κB, NLRP3 and IL-1β in the kidney. Harp was a promising anti-HUA agent. [Display omitted] • Harp exhibited remarkable amelioration effects on hyperuricemia and hyperuricemia-induced kidney injury. • Harp reduced uric acid production by acting as a potent XOD and ADA dual inhibitor. • Harp as an effective uricosuric agent to regulate the expressions of urate tansportation-associated proteins to enhance UA excretion. • Harp effectively attenuate UA-induced renal injury by regulating the NF-κB/NLRP3 pathway. [ABSTRACT FROM AUTHOR]

Hyperuricemia (HUA) is a metabolic disease characterized by the increase of serum uric acid (UA) level. Sargentodoxae Caulis (SC) is a commonly used herbal medicine for the treatment of gouty arthritis, traumatic swelling, and rheumatic arthritis in clinic. In this study, a total of fifteen compounds were identified in SC water extract using UHPLC-Q-TOF-MS/MS, including three phenolic acids, seven phenolic glycosides, four organic acids, and one lignan. Then, to study the hypouricemia effect of SC, a HUA mouse model was induced using a combination of PO, HX, and 20% yeast feed. After 14 days of treatment with the SC water extract, the levels of serum UA, creatinine (CRE), blood urea nitrogen (BUN) were reduced significantly, and the organ indexes were restored, the xanthine oxidase (XOD) activity were inhibited as well. Meanwhile, SC water extract could ameliorate the pathological status of kidneys and intestine of HUA mice. Additionally, quantitative real-time PCR (qRT-PCR) and western blotting results showed that SC water extract could increase the expression of ATP binding cassette subfamily G member 2 (ABCG2), organic cation transporter 1 (OCT1), organic anion transporter 1 (OAT1) and organic anion transporter 3 (OAT3), whereas decrease the expression of glucose transporter 9 (GLUT9). This study provided a data support for the clinical application of SC in the treatment of HUA. [Display omitted] [ABSTRACT FROM AUTHOR]

Phellodendri Chinese Cortex has long been used to treat hyperuricemia and gout. Berberine (BBR), its characteristic ingredient, has also been shown to be effective in alleviating monosodium urate crystals-triggered gout inflammation in vitro and in vivo. Dihydroberberine (DHB) is a hydrogenated derivative of BBR that showed improved in vivo efficacy on many metabolic disorders. However, its anti-hyperuricemia effect remains underexplored. In the present work, the hypouricemic and renoprotective effects of DHB on hyperuricemic mice were investigated. The hyperuricemic mice model was induced by intraperitoneal injection of potassium oxonate (PO, 300 mg/kg) combined with intragastric administration of hypoxanthine (HX, 300 mg/kg) for 7 days. Different dosages of DHB (25, 50 mg/kg), BBR (50 mg/kg) or febuxostat (Feb, 5 mg/kg) were orally given to mice 1 h after modeling. The molecular docking results showed that DHB effectively inhibited xanthine oxidase (XOD) by binding with its active site. In vitro, DHB exhibited significant XOD inhibitory activity (IC50 value, 34.37 μM). The in vivo results showed that DHB had obvious hypouricemic and renoprotective effects in hyperuricemic mice. It could not only lower the uric acid and XOD levels in serum, but also suppress the activities of XOD and adenosine deaminase (ADA) in the liver. Furthermore, DHB noticeably down-regulated the renal mRNA and protein expression of XOD. Besides, DHB remarkably and dose-dependently ameliorated renal damage, as evidenced by considerably reducing serum creatinine and blood urea nitrogen (BUN) levels, inflammatory cytokine (TNF-α, IL-1β, IL-6 and IL-18) levels and restoring kidney histological deteriorations. Further mechanistic investigation showed that DHB distinctly down-regulated renal mRNA and protein levels of URAT1, GLUT9, NOD-like receptor 3 (NLRP3), apoptosis-associated speck-like (ASC), caspase-1 and IL-1β. Our study revealed that DHB had outstanding hypouricemic and renoprotective effects via suppressing XOD, URAT1, GLUT9 and NLRP3 inflammasome activation in the kidney.

To develop a more effective and safer treatment for Hyperuricemia (HUA), this research investigated the anti-hyperuricemic mechanism of KGM from the perspectives of uric acid (UA) production and excretion in rat model. After four-week experiment, KGM at 168 mg/kg did best in reducing serum UA level. The mechanism of KGM improving HUA was related to its inhibitory capacity to the activities and mRNA expression of xanthine oxidase (XOD) and adenosine deaminase (ADA) in liver. Meanwhile, KGM could also down-regulate the protein expression of uric acid transporters1 (URAT1) and up-regulate the mRNA and protein expression of urate transporter (UAT), organic anion transporter1 (OAT1) and organic anion transporter3 (OAT3) in kidney. Moreover, KGM could also alleviate the renal dysfunction caused by HUA by mitigating urate deposition, and reducing serum creatinine (Cr) and blood urea nitrogen (BUN) levels. KGM might complement existing therapies to improve HUA.

Objectives: To investigate the antihyperuricemia and nephroprotective effects of Orthosiphon stamineus extracts on hyperuricemia (HUA) mice and explore the potential mechanisms. Methods: Orthosiphon stamineus extracts were extracted using 50% ethanol and enriched using ethyl acetate, and characterised utilising UPLC/ESI‐MS. A potassium oxonate (PO) induced hyperuricemic mouse model was used to evaluate antihyperuricemia and nephroprotective effects of O. stamineus ethyl acetate extracts (OSE). Key findings: Eight constituents from OSE were identified and OSE treatment ameliorated HUA by regulating key indicators of kidney dysfunction and xanthine oxidase, adenosine deaminase activity and urate transporters in hyperuricemic mice. Moreover, in renal histopathology analysis, OSE significantly alleviated kidney injury. Conclusions: These findings demonstrate that OSE has antihyperuricemic and nephroprotective effects on PO‐induced HUA mice and those results indicate that OSE could be a safe and effective agent or functional ingredient for treating HUA. [ABSTRACT FROM AUTHOR]

It is known that sunflower (Helianthus annuus L.) calathide enzymatically hydrolyzed extract (SCHE) contributes to the regulation of serum uric acid (UA); however, evidence regarding its bioactive components and mechanism are lacking. We identified two water-soluble components (scopoletin and chlorogenic acid) that are abundant in sunflower calathide, especially evaluated for the inhibition of xanthine oxidase (XO) and the expression levels of urate transporters with SCHE. Molecular docking of a chlorogenic acid–XO complex was more stable than that of the Scopoletin–XO, and its binding pockets, which closed the Mo = S center, was similar to xanthine pockets. Moreover, chlorogenic acid exhibited stronger inhibition than that of the scopoletin below 260 μM, despite the IC50 of scopoletin (577.7 μM) being lower than that chlorogenic acid (844.7 μM) on the UA generation assessed by a spectrophotometer in vitro. It revealed that chlorogenic acid and scopoletin were competitive inhibitors of XO. In addition, the SCHE (300 μg/mL) and chlorogenic acid (0.75 mM) obviously inhibited urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) expression levels, while scopoletin significantly upregulated the expression of GLUT9. To summarize, chlorogenic acid served a crucial role in UA regulation consistent with the SCHE and functioned as an important ingredient of SCHE. The strategic analysis of SCHE combined with scopoletin and chlorogenic acid may contribute to the development of food supplemental alternatives on UA metabolism and the reduction of agricultural byproduct waste.

The development of food-derived antihyperuricemic substances is important for alleviating hyperuricemia (HUA) and associated inflammation. Here, novel peptides from Thunnus albacares (TAP) with strong antihyperuricemic activity were prepared. TAP was prepared by alkaline protease (molecular weight <1000 Da), with an IC 50 value of xanthine oxidase inhibitory activity of 2.498 mg/mL, and 5 mg/mL TAP could reduce uric acid (UA) by 33.62% in human kidney-2 (HK-2) cells ( P < 0.01). Mice were fed a high-purine diet and injected with potassium oxonate to induce HUA. Oral administration of TAP (600 mg/kg/d) reduced serum UA significantly by 42.22% and increased urine UA by 79.02% ( P < 0.01) via regulating urate transporters GLUT9, organic anion transporter 1, and ATP-binding cassette subfamily G2. Meantime, TAP exhibited hepatoprotective and nephroprotective effects, according to histological analysis. Besides, HUA mice treated with TAP showed anti-inflammatory activity by decreasing the levels of toll-like receptor 4, nuclear factors-κB p65, NLRP3, ASC, and Caspase-1 in the kidneys ( P < 0.01). According to serum non-targeted metabolomics, 91 differential metabolites between the MC and TAP groups were identified, and purine metabolism was considered to be the main pathway for TAP alleviating HUA. In a word, TAP exhibited strong antihyperuricemic activity both in vitro and in vivo.

We presented an update in the field of hypouricemia, which is defined as a serum urate concentration of < 2 mg/dL (119 μmol/L), for the practicing rheumatologist, who usually is the consulting physician in cases of disorders of urate metabolism. We performed a narrative review through a literature search for original and review articles in the field of human hypouricemia published between January 1950 and July 2018. We divided the etiology of hypouricemia into two main categories: those associated with a decrease in urate production and those promoting the elimination of urate via the kidneys. The most common conditions associated with these categories are discussed. Furthermore, the etiology of hypouricemia may be associated with certain medications prescribed by the practicing rheumatologists, such as the following: urate-lowering drugs (allopurinol and febuxostat); recombinant uricase (pegloticase); uricosuric agents (probenecid, benzbromarone); urate transporter URAT1 inhibitor (lesinurad); angiotensin II receptor blocker (losartan); fenofibrate; high-dose trimethoprim-sulfamethoxazole; some NSAID; and high-dose salicylate therapy. The rheumatologist is considered an expert in the metabolism of urate and its associated pathological conditions. Therefore, specialists must recognize hypouricemia as a biomarker of various pathological and potentially harmful conditions, highlighting the importance of conducting a deeper clinical investigation to reach a more accurate diagnosis and treatment. [ABSTRACT FROM AUTHOR]

To investigate the effects of Pu-erh ripened tea on lowering uric acid levels and identify its possible mechanisms, three different doses of the tea, with allopurinol as a positive control, were administered intragastrically to hyperuricemic mice. Hyperuricemia was induced in the mice by oral administration of potassium oxonate for 7 days. Serum levels of uric acid, liver xanthine oxidase (XOD) and adenosine deaminase (ADA) activities, and expression of renal mURAT1, mGLUT9, mOAT1 and mOCT1 protein and mRNA were measured. Pu-erh ripened tea, at all doses, significantly lowered serum uric acid levels. At the high and medium doses, it also markedly inhibited liver XOD and ADA activities. Furthermore, mURAT1 and mGLUT9 expression levels were significantly down-regulated by Pu-erh ripened tea treatment. These results suggested that Pu-erh ripened tea can resist to hyperuricemia, possibly by inhibiting, concurrently, uric acid production and renal urate reabsorption.

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.

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Graphical abstract Highlights • KGM inhibits the activities of XOD and ADA in serum and liver. • KGM down-regulates mRNA expression of XOD and ADA in liver. • KGM up-regulates mRNA and protein expression of UAT, OAT1 and OAT3 in kidney. • KGM down-regulates protein expression of URAT1 in kidney. Abstract To develop a more effective and safer treatment for Hyperuricemia (HUA), this research investigated the anti-hyperuricemic mechanism of KGM from the perspectives of uric acid (UA) production and excretion in rat model. After four-week experiment, KGM at 168 mg/kg did best in reducing serum UA level. The mechanism of KGM improving HUA was related to its inhibitory capacity to the activities and mRNA expression of xanthine oxidase (XOD) and adenosine deaminase (ADA) in liver. Meanwhile, KGM could also down-regulate the protein expression of uric acid transporters1 (URAT1) and up-regulate the mRNA and protein expression of urate transporter (UAT), organic anion transporter1 (OAT1) and organic anion transporter3 (OAT3) in kidney. Moreover, KGM could also alleviate the renal dysfunction caused by HUA by mitigating urate deposition, and reducing serum creatinine (Cr) and blood urea nitrogen (BUN) levels. KGM might complement existing therapies to improve HUA. [ABSTRACT FROM AUTHOR]

Hyperuricemia is an important pathological basis of gout and a distinct hazard factor for metabolic syndromes and cardiovascular and chronic renal disease, but lacks safe and effective treatments currently. Paeonia × suffruticosa Andrews leaf effectively reduced serum uric acid in gout patients; however, the material foundation and the mechanism remain unclear. To determine the primary active components and mechanism of P. suffruticosa leaf in hyperuricemic mice. The chemical constituents of P. suffruticosa leaf was identified using high-performance liquid chromatographic analysis. The anti-hyperuricemic activity of P. suffruticosa leaf extract (12.5, 25, 50, 100, and 200 mg/kg) and its components was evaluated in hyperuricemic mice induced by a high purine diet for 14 days. Then, the urate-lowering effects of apigenin 7 -O- glucoside (0.09, 0.18, and 0.36 mg/kg) were assessed in another hyperuricemic mice model built by administrating potassium oxonate and adenine for 4 weeks. The inhibitory effect of apigenin 7 -O- glucoside on uric acid production was elucidated by investigating xanthine oxidase activity in vitro and in serum and the liver and through molecular docking. Immunofluorescence and western blot analyses of the expression of renal urate transporter 1 (URAT1), glucose transporter 9 (GLUT9), organic anion transporters 1 (OAT1), and ATP-binding cassette G member 2 (ABCG2) proteins elucidated how apigenin 7 -O- glucoside promoted uric acid excretion. Six compounds were identified in P. suffruticosa leaf: gallic acid, methyl gallate, oxypaeoniflorin, paeoniflorin, galloylpaeoniflorin, and apigenin 7 -O- glucoside. P. suffruticosa leaf extract significantly attenuated increased serum uric acid, creatinine, and xanthine oxidase activity in hyperuricemic mice. Apigenin 7 -O- glucoside from P. suffruticosa leaf reduced uric acid, creatinine, and malondialdehyde serum levels, increased superoxide dismutase activity, and partially restored the spleen coefficient in hyperuricemic mice. Apigenin 7 -O- glucoside inhibited xanthine oxidase activity in vitro and decreased serum and liver xanthine oxidase activity and liver xanthine oxidase protein expression in hyperuricemic mice. Molecular docking revealed that apigenin 7 -O- glucoside bound to xanthine oxidase. Apigenin 7 -O- glucoside facilitated uric acid excretion by modulating the renal urate transporters URAT1, GLUT9, OAT1, and ABCG2. Apigenin 7 -O- glucoside protected against renal damage and oxidative stress caused by hyperuricemia by reducing serum creatinine, blood urea nitrogen, malondialdehyde, and renal reactive oxygen species levels; increasing serum and renal superoxide dismutase activity; restoring the renal coefficient; and reducing renal pathological injury. Apigenin 7 -O- glucoside is the main urate-lowering active component of P. suffruticosa leaf extract in the hyperuricemic mice. It suppressed liver xanthine oxidase activity to decrease uric acid synthesis and modulated renal urate transporters to stimulate uric acid excretion, alleviating kidney damage caused by hyperuricemia. [Display omitted] [ABSTRACT FROM AUTHOR]

Objective The current study aimed to investigate whether the saponins, bioactive component of effects of D. collettii , could reduce the serum uric acid level in a hyperuricemic mouse via regulation of urate transporters. Methods Chronic hyperuricemia model was established by combine administration of adenine (100 mg/kg) and ethambutol (250 mg/kg). In the model group, the serum uric acid (SUA), urine uric acid (UUA) volume, and 24-h UUA values increased significantly, while the uric acid clearance rate (CUr) and creatinine clearance rate (CCr) values decreased. Further, the model groups showed significantly lower expression of organic anion transporter 1 (OAT1) and organic anion transporter 3 (OAT3) and significantly higher expression of renal tubular urate transporter 1 (URAT1), glucose transporter 9 (GLUT9) and URAT1 mRNA than the normal control group. Results Saponins administration was found to have a dose-dependent effect, as evidenced by the increase in the 24-h UUA, CUr and CCr values; the decrease in SUA; the decrease in the renal expression of URAT1 mRNA and URAT1 and GLUT9 proteins; and the increase in the renal expression of the OAT1 and OAT3 proteins. Conclusion The saponins extracted from D. collettii rhizomes had an obvious anti-hyperuricemic effect through downregulation of the URAT1 mRNA and the URAT1 and GLUT9 proteins and upregulation of the OAT1 and OAT3 proteins. [ABSTRACT FROM AUTHOR]

Accumulating data indicate that renal uric acid (UA) handling is altered in diabetes and by hypoglycemic agents. In addition, hyperinsulinemia is associated with hyperuricemia and hypouricosuria. However, the underlying mechanisms remain unclear. In this study, we aimed to investigate how diabetes and hypoglycemic agents alter the levels of renal urate transporters. In insulin-depleted diabetic rats with streptozotocin treatment, both UA excretion and fractional excretion of UA were increased, suggesting that tubular handling of UA is altered in this model. In the membrane fraction of the kidney, the expression of urate transporter 1 (URAT1) was significantly decreased, whereas that of ATP-binding cassette subfamily G member 2 (ABCG2) was increased, consistent with the increased renal UA clearance. Administration of insulin to the diabetic rats decreased UA excretion and alleviated UA transporter-level changes, while sodium glucose cotransporter 2 inhibitor (SGLT2i) ipragliflozin did not change renal UA handling in this model. To confirm the contribution of insulin in the regulation of urate transporters, normal rats received insulin and separately, ipragliflozin. Insulin significantly increased URAT1 and decreased ABCG2 levels, resulting in increased UA reabsorption. In contrast, the SGLT2i did not alter URAT1 or ABCG2 levels, although blood glucose levels were similarly reduced. Furthermore, we found that insulin significantly increased endogenous URAT1 levels in the membrane fraction of NRK-52E cells, the kidney epithelial cell line, demonstrating the direct effects of insulin on renal UA transport mechanisms. These results suggest a previously unrecognized mechanism for the anti-uricosuric effects of insulin and provide novel insights into the renal UA handling in the diabetic state. [ABSTRACT FROM AUTHOR]

Gout, arthritis urica, is a metabolic disorder caused by an inflammatory reaction to the deposition of urate crystals into joints and soft tissues. Chronic hyperuricaemia, the cause of the gout, results in an imbalance between endogenous production and excretion of uric acid. The most common mechanism leading to hyperuricaemia is decreased excretion of uric acid. Urate transport is a complex process involving a number of transmembrane proteins that provide reabsorption (mostly URAT1, GLUT9) and secretion (ABCG2) on the apical and basolateral side of the proximal tubules. ABCG2, with a significant proportion, provides transport in the gastrointestinal tract. New knowledge on uric acid excretion has allowed the development of a new strategy in the treatment of hyperuricaemia by blocking urate transporters. Knowledge of the genetic background of uricemia is essential for early identification of the aetiology of the disease, the choice of appropriate treatment, and also the monitoring of compliance by the patient. Detailed examination of purine metabolism and uric acid excretion in specialized laboratories is particularly useful for patients with early onset and / or familial outbreaks of the disease. [ABSTRACT FROM AUTHOR]

Guluronate oligosaccharides (GOS) is a biologically active natural product derived from brown algae. This study aimed to evaluate the amelioration of hyperuricemia and renal inflammation by GOS and its mechanisms. According to the results, GOS treatment reduced the serum uric acid (UA) and blood urea nitrogen (BUN) levels among hyperuricemic mice by 19.6% and 21.5% (P <0.05), at the same time, serum xanthine oxidase (XOD) and adenosine deaminase (ADA) levels were down-regulated to normal. GOS treatment ameliorated the renal pathologization associated with hyperuricemia and reduced renal IL-1β, IL-12, and IL-18 (P <0.05), suggesting a mitigating effect of GOS on renal damage. In addition, GOS supplementation modulates the mRNA levels of renal and intestinal urate transporters to promote uric acid excretion. GOS reversed the intestinal microbiota of hyperuricemic mice, significantly down-regulating the abundances of pernicious bacteria like Bilophila and Tuzzerella , while up-regulating the beneficial intestinal bacteria including Muribaculum , Lachnospiraceae_UCG_006 , Ruminococcus , Faecalibaculum , and Lachnospiraceae_NK4A136_group. Together, guluronate oligosaccharides can improve hyperuricemia by alleviating hyperuricemia-induced renal damage and reversing intestinal microbiota disorders. These findings provide evidence supporting the further development of guluronate oligosaccharides as a novel functional food ingredient suitable for hyperuricemia. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • A novel mouse model of hyperuricemia combined with gouty arthritis was established. • Polydatin not only reduced uric acid, but also had anti-gouty arthritis effects. • Polydatin regulated urate transporters, NLRP3 inflammasome and NF-κB pathway. • Polydatin had more advantages in treating hyperuricemia and gouty arthritis. Gout is a metabolic disease that seriously affects people's health. Polydatin, a stilbene compound isolated from Polygonum cuspidatum , has attracted much attention because of its rich biological activity and high safety. This study aimed to investigate the therapeutic effect and mechanism of polydatin on hyperuricemia (HUA) combined with gouty arthritis (GA). The results showed that polydatin reduced the levels of uric acid and inflammatory cytokines, indicating that polydatin had the effect of reducing uric acid and anti-GA. Then the inhibitors of ABCG2, NLRP3 inflammasome and NF-κB pathway (Ko143, MCC950 and QNZ) were used to demonstrate that polydatin played a role in reducing uric acid and anti-GA via regulating urate transporters, NLRP3 inflammasome and NF-κB pathway. Taken together, these results provided evidence that polydatin might be used as a potential functional ingredient for the synchronous treatment of HUA and GA. [ABSTRACT FROM AUTHOR]

To investigate the effects of Pu-erh ripened tea on lowering uric acid levels and identify its possible mechanisms, three different doses of the tea, with allopurinol as a positive control, were administered intragastrically to hyperuricemic mice. Hyperuricemia was induced in the mice by oral administration of potassium oxonate for 7 days. Serum levels of uric acid, liver xanthine oxidase (XOD) and adenosine deaminase (ADA) activities, and expression of renal mURAT1, mGLUT9, mOAT1 and mOCT1 protein and mRNA were measured. Pu-erh ripened tea, at all doses, significantly lowered serum uric acid levels. At the high and medium doses, it also markedly inhibited liver XOD and ADA activities. Furthermore, mURAT1 and mGLUT9 expression levels were significantly down-regulated by Pu-erh ripened tea treatment. These results suggested that Pu-erh ripened tea can resist to hyperuricemia, possibly by inhibiting, concurrently, uric acid production and renal urate reabsorption. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Green tea is a Chinese materia medica with the main functions of “inducing urination and quenching thirst”. Green tea polyphenols (GTP) are generally acknowledged as the main active fraction with multiple pharmacological functions in green tea. However, the effect of GTP on hyperuricemia is not clear till now. Aim of study The present study was carried out to investigate the effect of GTP on serum level of uric acid in potassium oxonate (PO)-induced hyperuricemic mice, and explore the underlying mechanisms from two aspects of production and excretion of uric acid. Materials and methods PO and GTP were intragastricly administered to mice for consecutive 7 days. Serum level of uric acid, and xanthine oxidase (XOD) activity in serum and liver were examined. Simultaneously, expression of XOD protein in liver was analyzed by Western blot assay. Expressions of urate transporters including urate-anion transporter (URAT) 1, organic anion transporter (OAT) 1 and 3 in kidney were analyzed by immunohistochemistry staining method. Results 300 and 600 mg/kg GTP significantly decreased serum level of uric acid of hyperuricemic mice in a dose-dependent manner ( p <0.05 or p <0.01). Besides, 300 and 600 mg/kg GTP markedly reduced XOD activity in serum and liver of hyperuricemic mice (both p <0.01). Furthermore, 300 and 600 mg/kg GTP clearly reduced XOD expression in liver, as well as reduced URAT1 expression and increased OAT1 and OAT3 expressions in kidney of hyperuricemic mice ( p <0.05 or p <0.01). Conclusions These results demonstrated that GTP had the effect of lowering uric acid through decreasing the uric acid production and increasing uric acid excretion. Our study suggested that GTP would be a promising candidate as a novel hypouricaemic agent for further investigation. [ABSTRACT FROM AUTHOR]

Gout is the most common inflammatory arthropathy and occurs in the setting of elevated serum urate levels. Gout is also known to be associated with multiple comorbidities including cardiovascular disease and the metabolic syndrome. Recent advances in research have increased our understanding and improved our knowledge of the pathophysiology of gout. Genome-wide association studies have permitted the identification of several new and common genetic factors that contribute to hyperuricemia and gout. Most of these are involved with the renal urate transport system (the uric acid transportasome), generally considered the most influential regulator of serum urate homeostasis. Thus far, SCL22A12, SCL2A9, and GLUT9 have been found to have the greatest variation and most influence on serum urate levels. However, genetics are only a part of the explanation in the development of hyperuricemia and gout. As results have been mixed, the role of known urate influential genes in gout's associated comorbidities remains unclear. Regardless, GWAS findings have expanded our understanding of the pathophysiology of hyperuricemia and gout, and will likely play a role in the development of future therapies and treatment of this ancient disease. [ABSTRACT FROM AUTHOR]

Diet plays a significant role in the development of gout and hyperuricemia. Gout and hyperuricemia have likewise been associated with the development of cardiovascular disease and metabolic syndrome. Epidemiological studies have shown that certain foods influence levels of serum uric acid and the risk for development of gout.This article reviews the influence of dietary factors on serum uric acid levels and risk of gout, as well as the role of urate transporters in the development of hyperuricemia and gout.Various epidemiological studies have shown the effects of certain foods on the risk of developing gout and hyperuricemia. Low-fat dairy products, purine-rich vegetables, whole grains, nuts and legumes, and less sugary fruits, coffee and vitamin C supplements decrease the risk, whereas intake of red meat, fructose-containing beverages and alcohol increase the risk of gout. There is also an increased although basic understanding of the effects of vitamin C, alcohol and fructose on urate transporters. Certain foods can lead to a decreased or increased risk of development of gout and hyperuricemia. Advances have established the interplay of certain foods on urate transporters and renal handling of urate. More studies, especially prospective ones, are needed to increase our understanding of the roles of foods and urate transporters and other molecular mechanisms on the risk of developing gout and hyperuricemia. [ABSTRACT FROM AUTHOR]

Hyperuricemia causes gouty arthritis, kidney disease, heart disease, and other diseases. Xanthine oxidase (XOD) and urate transporters play important roles in urate homeostasis. Numerous plants have been identified as XOD inhibitors. Longan seeds are known to contain high levels of polyphenols such as corilagin, gallic acid and ellagic acid. We examined the effect of longan seed extract on XOD inhibition and urate transporters GLUT1 and GLUT9 using both in vitro and in vivo assays. The results showed that dried longan seed extract (LSE) and its active components inhibited XOD dose-dependently in vitro. LSE inhibited uric acid production and XOD activity in normal liver cells (clone-9 cells) and was not cytotoxic under the concentration of 200 μg/ml. For the in vivo study, Sprague-Dawley (SD) rats were given intraperitoneally for thirty minutes with or without allopurinol (a XOD inhibitor, 3.5 mg/kg) or LSE (80 mg/kg) and then injected intraperitioneally with 250 mg/kg of oxonic acid and 300 mg/kg of hypoxanthine intragastrically. LSE was able to reduce serum uric acid level and XOD activity in hyperuricemic rats. However, LSE or allopurinol did not inhibit the liver XOD activities. On the other hand, GLUT1 protein was suppressed in kidney and GLUT9 was induced in liver from experimental rats and LSE or allopurinol decreased GLUT9 but increased GLUT1 protein level in the liver and kidney, respectively. These results confirmed the claimed effect of longan seeds on gout and other complications and suggested that its urate reducing effect might be due to modulation of urate transporters and inhibition of circulating xanthine oxidase. [ABSTRACT FROM AUTHOR]

Urate is the final metabolite of purine in humans. Renal urate handling is clinically important because under-reabsorption or underexcretion causes hypouricemia or hyperuricemia, respectively. We have identified a urate-anion exchanger, URAT1, localized at the apical side and a voltage-driven urate efflux transporter, URATv1, expressed at the basolateral side of the renal proximal tubules. URAT1 and URATv1 are vital to renal urate reabsorption because the experimental data have illustrated that functional loss of these transporter proteins affords hypouricemia. While mutations affording enhanced function via these transporter proteins on urate handling is unknown, we have constructed kidney-specific transgenic (Tg) mice for URAT1 or URATv1 to investigate this problem. In our study, each transgene was under the control of the mouse URAT1 promoter so that transgene expression was directed to the kidney. Plasma urate concentrations in URAT1 and URATv1 Tg mice were not significantly different from that in wild-type (WT) mice. Urate excretion in URAT1 Tg mice was similar to that in WT mice, while URATv1 Tg mice excreted more urate compared with WT. Our results suggest that hyperfunctioning URATv1 in the kidney can lead to increased urate reabsorption and may contribute to the development of hyperuricemia. [ABSTRACT FROM PUBLISHER]

The ability to take up and metabolize glucose at the cellular level is a property shared by the vast majority of existing organisms. Most mammalian cells import glucose by a process of facilitative diffusion mediated by members of the Glut (SLC2A) family of membrane transport proteins. Fourteen Glut proteins are expressed in the human and they include transporters for substrates other than glucose, including fructose, myoinositol, and urate. The primary physiological substrates for at least half of the 14 Glut proteins are either uncertain or unknown. The well-established glucose transporter isoforms, Gluts 1-4, are known to have distinct regulatory and/or kinetic properties that reflect their specific roles in cellular and whole body glucose homeostasis. Separate review articles on many of the Glut proteins have recently appeared in this journal. Here, we provide a very brief summary of the known properties of the 14 Glut proteins and suggest some avenues of future investigation in this area. [ABSTRACT FROM AUTHOR]

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. [Display omitted] • Berberrubine possessed anti-hyperuricemic and nephroprotective effects in PO/HX-induced HUA. • Berberrubine regulated urate transporter expressions and JAK2/STAT3 signaling pathway. • Berberrubine might be the main active metabolite of BBR for its anti-HUA effect. • Berberrubine served as a potential therapeutic candidate for the treatment of HUA. [ABSTRACT FROM AUTHOR]

Phellodendri Chinese Cortex has long been used to treat hyperuricemia and gout. Berberine (BBR), its characteristic ingredient, has also been shown to be effective in alleviating monosodium urate crystals-triggered gout inflammation in vitro and in vivo. Dihydroberberine (DHB) is a hydrogenated derivative of BBR that showed improved in vivo efficacy on many metabolic disorders. However, its anti-hyperuricemia effect remains underexplored. In the present work, the hypouricemic and renoprotective effects of DHB on hyperuricemic mice were investigated. The hyperuricemic mice model was induced by intraperitoneal injection of potassium oxonate (PO, 300 mg/kg) combined with intragastric administration of hypoxanthine (HX, 300 mg/kg) for 7 days. Different dosages of DHB (25, 50 mg/kg), BBR (50 mg/kg) or febuxostat (Feb, 5 mg/kg) were orally given to mice 1 h after modeling. The molecular docking results showed that DHB effectively inhibited xanthine oxidase (XOD) by binding with its active site. In vitro , DHB exhibited significant XOD inhibitory activity (IC50 value, 34.37 μM). The in vivo results showed that DHB had obvious hypouricemic and renoprotective effects in hyperuricemic mice. It could not only lower the uric acid and XOD levels in serum, but also suppress the activities of XOD and adenosine deaminase (ADA) in the liver. Furthermore, DHB noticeably down-regulated the renal mRNA and protein expression of XOD. Besides, DHB remarkably and dose-dependently ameliorated renal damage, as evidenced by considerably reducing serum creatinine and blood urea nitrogen (BUN) levels, inflammatory cytokine (TNF-α, IL-1β, IL-6 and IL-18) levels and restoring kidney histological deteriorations. Further mechanistic investigation showed that DHB distinctly down-regulated renal mRNA and protein levels of URAT1, GLUT9, NOD-like receptor 3 (NLRP3), apoptosis-associated speck-like (ASC), caspase-1 and IL-1β. Our study revealed that DHB had outstanding hypouricemic and renoprotective effects via suppressing XOD, URAT1, GLUT9 and NLRP3 inflammasome activation in the kidney. [ABSTRACT FROM AUTHOR]