Hepatic Xanthine Oxidase Activity Research Articles

Lychee Peel Extract Ameliorates Hyperuricemia by Regulating Uric Acid Production and Excretion in Mice

Lychee peel generated during the industrial processing of lychee fruit are currently disposed of as agricultural waste. This study investigates the primary components of lychee peel extract (LPE) and the regulatory mechanisms of LPE on reducing uric acid (UA). Mice were injected with hypoxanthine and potassium oxonate to induce hyperuricemia and concurrently orally administered LPE. The analysis of the LPE composition reveals a predominance of polyphenolic compounds, including (-)-epicatechin, (-)-epigallocatechin, and procyanidin A2. In vitro tests have demonstrated that the LPE significantly inhibits the activity of xanthine oxidase (XOD). In vivo studies showed that LPE can reduce UA levels in hyperuricemia mice. Further mechanistic insights indicate that LPE inhibits hepatic XOD activity, thereby reducing UA synthesis within the organism. It also decreases the protein expression of urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9), which leads to diminished UA reabsorption and increased excretion of UA. Additionally, LPE enhances the activity of superoxide dismutase (SOD) while simultaneously reducing malondialdehyde (MDA) contents, thereby improving antioxidant capacity in mice. Our findings indicate that LPE not only inhibits the production of UA but also promotes its elimination, positioning it as a promising candidate for UA-lowering agents.

Anti-hyperuricemic effects of the seeds of Hovenia acerba in hyperuricemia mice

Ethnopharmacological relevanceThe seeds of Hovenia acerba water extract (HAW) are used as an edible traditional Chinese medicine to treat diseases related to hyperuricemia (HUA). Aim of the studyTo evaluate HAW for its anti-HUA effect and to figure out their underlying mechanisms. Materials and methodsThe anti-HUA effects were evaluated on a mouse model by testing HAW’s effects on the levels of serum uric acid (SUA), the biochemical indicators of liver and kidney function, and the histology of liver and kidney. Body weight and organ coefficients were determined for safety evaluation. RT-qPCR, Western blot and transcriptomic analysis was applied to investigate key mRNAs, proteins and signaling pathways. ResultsHAW significantly reduced the serum levels of UA, ALT, AST, and xanthine oxidase (XOD) and histologically alleviated the liver damage in HUA mice with no negative effect on body weight and organ coefficients. HAW markedly inhibited hepatic XOD activity and protein expression, significantly down-regulated mRNA and protein expressions of urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9), and up-regulated those of ATP transporter G2 (ABCG2) and renal organic anion transporter 1 (OAT1). RNA-seq analysis showed that 248 HUA-induced differential expression genes (DEGs) were reversed by HAW in the kidney. qRT-PCR analysis showed that regulation of the expressions of HUA-related inflammatory genes were involved. ConclusionHAW possessed remarkable anti-HUA effect. The mechanism involved XOD inhibition to reduce uric acid production, up-regulation of ABCG2 and OAT1 to increase uric acid excretion, and down-regulation of GLUT9 and URAT1 to inhibit uric acid reabsorption, and regulation of HUA-related inflammatory genes.

Integrating metabolomics with network pharmacology to reveal the mechanism of Poria cocos in hyperuricemia treatment

Ethnopharmacological relevanceHyperuricemia is a chronic condition characterized by persistently elevated uric acid levels, often leading to gouty arthritis and renal insufficiency. Poria cocos F.A.Wolf, a traditional Chinese medicinal herb, possesses notable diuretic and anti-inflammatory properties and is widely used to treat edema, inflammation, viral infections, and tumors. Recent studies suggest that Poria cocos has the potential to lower uric acid levels and mitigate kidney damage, making it a promising candidate for hyperuricemia treatment. However, its pharmacological mechanisms require further exploration. Aim of the studyThis study aims to elucidate the mechanisms by which Poria cocos alleviates hyperuricemia, using metabolomics and network pharmacology approaches. Materials and methodsHyperuricemia was induced in rats via a high-yeast diet combined with potassium oxonate. The effects of Poria cocos were assessed by measuring serum uric acid, creatinine, urea nitrogen levels, hepatic xanthine oxidase activity, and renal tissue morphology. Non-targeted metabolomics was employed to identify differential metabolites and explore the metabolic pathways involved in its therapeutic effects. Network pharmacology was utilized to analyze potential targets and signaling pathways, which were validated through molecular docking and ELISA analysis. ResultsPoria cocos extract significantly reduced serum uric acid, creatinine, and urea nitrogen levels, inhibited xanthine oxidase activity, and attenuated kidney damage. Metabolomics combined with network pharmacology identified xanthine dehydrogenase and fatty acid synthase as key targets, while purine metabolism, fatty acid biosynthesis, and primary bile acid biosynthesis were identified as critical pathways. ELISA confirmed that Poria cocos suppressed xanthine dehydrogenase and fatty acid synthase expression in hyperuricemic rats. Molecular docking further verified strong binding interactions between core compounds and key targets. ConclusionsPoria cocos alleviates hyperuricemia by modulating multiple compounds, targets, and pathways. Through network pharmacology and metabolomics, it reveals that Poria cocos selectively regulates xanthine dehydrogenase and fatty acid synthase, influencing purine metabolism, fatty acid biosynthesis, and primary bile acid biosynthesis pathways. These findings provide insights into its therapeutic mechanisms, supporting the clinical application of Poria cocos in treating metabolic disorders and kidney damage associated with hyperuricemia.

Salinomycin, a potent inhibitor of XOD and URAT1, ameliorates hyperuricemic nephropathy by activating NRF2, modulating the gut microbiota, and promoting SCFA production

Long-term hyperuricemia can induce kidney damage, clinically referred to as hyperuricemic nephropathy (HN), which is characterized by renal fibrosis, inflammation, and oxidative stress. However, currently used uric acid-lowering drugs are not capable of protecting the kidneys from damage. Therefore, uric acid-lowering drugs that can also protect the kidneys are urgently needed. In this study, we first discovered that salinomycin, an antibiotic, can regulate uric acid homeostasis and ameliorate kidney damage in mice with HN. Mechanistically, salinomycin inhibited serum and hepatic xanthine oxidase (XOD) activities and downregulated renal urate transporter 1 (URAT1) expression and transport activity, thus exerting uric acid-lowering effects in mice with HN. Furthermore, we found that salinomycin promoted p-NRF2 Ser40 expression, resulting in increased nuclear translocation of NRF2 and activation of NRF2. More importantly, salinomycin affected the gut microbiota and promoted the generation of short-chain fatty acids (SCFAs) in mice with HN. In conclusion, our results revealed that salinomycin maintains uric acid homeostasis and alleviates kidney injury in mice with HN by multiple mechanisms, suggesting that salinomycin might be a desirable candidate for HN treatment in the clinic.

Investigating the effects of rare ginsenosides on hyperuricemia and associated sperm damage via nontargeted metabolomics and gut microbiota

Ethnopharmacological relevanceIn ancient times, ginseng was used for hyperuricemia treatment as described in the classic traditional Chinese medical text Shang Han Lun. Recent studies have shown that common ginsenosides and rare ginsenosides (RGS) are the main active compounds in ginseng. RGS have higher activity and are less studied in the treatment of hyperuricemia. Aim of the studyTo determine whether RGS prevents and ameliorates potassium oxonate(PO)-induced hyperuricemia and concomitant spermatozoa damage in mice and the possible underlying mechanisms. Materials and methodsPotassium oxonate (PO, 300 mg/kg) induced hyperuricemia in mice via the oral administration of RGS (50, 100, or 200 mg/kg) or allopurinol (ALL, 5 mg/kg) for 35 days. Uric acid (UA) and xanthine oxidase (XO) levels were measured to assess the degree of histopathological damage in the liver, kidney, and testis, and renal creatinine (CRE), urea nitrogen (BUN), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), and inflammatory factor (IL-1β) levels were measured to calculate the sperm density. Mechanisms were also explored based on blood and urine metabolomics and the gut microbiota. ResultsIn this study, we demonstrated that RGS containing Rg3, Rk1, Rg6, and Rg5 could reduce serum UA levels, inhibit serum and hepatic XO activity, reduce renal CRE and BUN levels, further restore renal SOD and GSH activities, reduce the accumulation of MDA in the kidneys, and attenuate the production of renal IL-1β. RGS was able to restore sperm density. Metabolomic analysis revealed that RGS improved sphingolipid metabolism, pyrimidine metabolism, and other metabolic pathways. 16S rDNA sequencing revealed that RGS could increase gut microbial diversity, restore the Firmicutes/Bacteroidetes (F/B) ratio, and adjust the intestinal microbial balance. Spearman's correlation analysis revealed a correlation between differentially metabolites and the gut microbiota. Lactobacillus and Akkermansia are the core genera. ConclusionRGS can be a candidate for the prevention and amelioration of hyperuricemia and concomitant sperm damage. Its mechanism of action is closely related to sphingolipid metabolism, pyrimidine metabolism, and the modulation of gut microbiota, such as Lactobacillus and Akkermansia.

Preventive effect of Lactobacillus johnsonii YH1136 against uric acid accumulation and renal damages.

Hyperuricemia (HUA) is a prevalent metabolic disorder whose development is associated with intestinal microbiota. Therefore, probiotics have emerged as a potential and safe approach for lowering uric acid (UA) levels. However, the underlying mechanisms of many effective probiotic strains remain unknown. C57BL/6 mice were randomly divided into two groups: control and model groups. The model group received 12 weeks of potassium oxonate. Through 16s sequencing we found that HUA resulted in a significant decrease in the total diversity of all intestinal segments. When each intestinal segment was analyzed individually, the reduction in diversity was only significant in the cecum and colon sections. RDA analysis showed that lactobacilli in the rat colon exhibited a strong correlation with model group, suggesting that Lactobacillus may play an important role in HUA. Consequently, the preventive effects of Lactobacillus johnsonii YH1136 against HUA were investigated. C57BL/6 mice were randomly divided into three groups: control, model and YH1136 groups. The results showed that administering Lactobacillus johnsonii YH1136 effectively reduced serum UA levels in vivo by inhibiting hepatic xanthine oxidase (XOD) activity and promoting renal ABCG2 transporter expression. Moreover, supplementation with Lactobacillus johnsonii YH1136 significantly ameliorated pathological damage in the kidney and liver, thereby reducing UA accumulation. Hyperuricemia is accompanied by an altered composition of multiple gut bacteria, of which Lactobacillus is a key genus. Lactobacillus johnsonii YH1136 may ameliorate renal involvement in HUA via the gut-kidney axis.

Cinnamon essential oil based on NLRP3 inflammasome and renal uric acid transporters for hyperuricemia

Cinnamon is widely used as a medicinal herb and a culinary spice. The major bioactive component of cinnamon is cinnamon essential oil (CEO). CEO has been reported to have anti-inflammatory and antioxidant effects, but its mechanism of action is not known. In this study, metabolomics was combined with “weighting coefficients” from network pharmacology to identify key pathways and targets, differential metabolites and key metabolic pathways for the therapeutic effects of CEO on Hyperuricemia (HUA), and to precisely investigate the molecular mechanisms of the therapeutic effects of CEO on HUA. Metabolomic analysis revealed that abnormal l-glutamate metabolism and dysregulation of Arachidonic acid (AA) metabolic pathways exacerbated inflammatory responses and oxidative stress, subsequently mediating pathological changes in HUA and exacerbating renal tissue damage. Pharmacodynamic validation showed that CEO alleviated the renal inflammatory response by inhibiting hepatic xanthine oxidase activity, upregulating superoxide dismutase and glutathione peroxidase levels, and downregulating malondialdehyde levels, synergistically inhibiting NLRP3 inflammasome activation, suppressing downstream inflammatory Interleukin-1 beta (IL-1β) and Interleukin-18 (IL-18) secretion, and enhancing antioxidant levels. Additionally, CEO exerted renal protective effects by upregulating the renal transporters OAT1 and ABCG2 and downregulating the GLUT9 and URAT1 levels, resulting in the downregulation of uric acid production and the alleviation of renal tubular lesions. This suggests that CEO could be considered as a potential functional food for kidney damage caused by hyperuricemia.

Artemisia selengensis Turcz. leaves extract ameliorates hyperuricemia in mice by inhibiting hepatic xanthine oxidase activity, modulating renal uric acid transporters, and improving metabolic disorders

Artemisia selengensis Turcz. (AST) is a common edible and medicinal herb with multiple health benefits. Our previous research indicated that AST leaves, by-products of AST, possess strong in vitro xanthine oxidase (XOD) inhibitory activity, making them a potential treatment for hyperuricemia (HUA). In this study, we investigated the anti-HUA effect of AST leaves extract (ASTLE) in HUA mice and explore the underlying mechanisms. Chemical analysis showed that ASTLE is rich in caffeoylquinic acids (CQAs), including four mono-CQAs (1-CQA, 3-CQA, 5-CQA, and 4-CQA) and six di-CQAs (1,3-diCQA, 1,4-diCQA, 3,4-diCQA, 1,5-diCQA, 3,5-diCQA, and 4,5-diCQA). In HUA mice, ASTLE reduced serum uric acid level and increased urine uric acid level and fraction excretion of uric acid. ASTLE also protected against liver and kidney damage, as evidenced by decreased serum levels of glutamic oxaloacetic transaminase, glutamic-pyruvic transaminase, creatinine, and blood urea nitrogen. After ASTLE intervention, the hepatic XOD activity was inhibited. Additionally, the mRNA expression of mURAT1 and mGLUT9 was down-regulated, while the mRNA expression of mABCG2, mOAT1, and mOAT3 was up-regulated. Metabolomic analysis further suggested that ASTLE mainly regulated amino acids and their metabolites, which are associated with renal uric acid excretion function. These results demonstrate that ASTLE rich in CQAs, has beneficial effects against HUA in mice by inhibiting hepatic XOD activity, modulating the mRNA expression of renal uric acid transporters, and improving metabolic disorders in HUA mice. Our findings suggest that AST leaves may be a promising natural resource for ameliorating HUA.

Pharmacological evaluation of a novel skeleton compound isobavachin (4′,7-dihydroxy-8-prenylflavanone) as a hypouricemic agent: Dual actions of URAT1/GLUT9 and xanthine oxidase inhibitory activity

Previously we discovered a novel natural scaffold compound, isobavachin (4′, 7-dihydroxy-8-prenylflavanone), as a potent URAT1 inhibitor by shape and structure based on a virtue screening approach. In this study, further urate-lowering mechanism, pharmacokinetics and toxicities of isobavachin were conducted. Isobavachin inhibited URAT1 with an IC50 value of 0.24 ± 0.06 μM, and residues S35, F365, I481 and R477 of URAT1 contributed to high affinity for isobavachin. Isobavachin also inhibited glucose transporter 9 (GLUT9), another pivotal urate reabsorption transporter, with an IC50 value of 1.12 ± 0.26 μM. Molecular docking and MMGBSA results indicated that isobavachin might compete residues R171, L75 and N333 with uric acid, which leads to inhibition of uric acid transport of GLUT9. Isobavachin weakly inhibited urate secretion transporters OAT1 with an IC50 value of 4.38 ± 1.27 μM, OAT3 with an IC50 of 3.64 ± 0.62 μM, and ABCG2 with an IC50 of 10.45 ± 2.17 μM. Isobavachin also inhibited xanthine oxidase (XOD) activity in vitro with an IC50 value of 14.43 ± 3.56 μM, and inhibited the hepatic XOD activities at 5–20 mg/kg in vivo. Docking and MMGBSA analysis indicated that isobavachin might bind to the Mo-Pt catalyze center of XOD, which leads to inhibition of uric acid production. In vivo, isobavachin exhibited powerful urate-lowering and uricosuric effects at 5–20 mg/kg compared with the positive drugs morin (20 mg/kg) and RDEA3170 (10 mg/kg). Safety assessments revealed that isobavachin was safe and had no obvious toxicities. Isobavachin has little cell toxicity in HK2 cells as indicated by the MTT assay. In vivo, after treatment with 50 mg/kg isobavachin for 14 days, isobavachin had little renal toxicity, as revealed by serum CR/BUN levels, and no hepatotoxicity as revealed by ALT/AST levels. Further HE examination also suggests that isobavachin has no obvious kidney/liver damage. A pharmacokinetic study in SD rats indicated isobavachin had lower bioavailability (12.84 ± 5.13 %) but long half-time (7.04 ± 2.68 h) to maintain a continuous plasma concentration. Collectively, these results indicate that isobavachin deserves further investigation as a candidate anti-hyperuricemic drug with a novel mechanism of action: selective urate reabsorption inhibitor (URAT1/GLUT9) with a moderate inhibitory effect on XOD.

Anti-Hyperuricemic, Nephroprotective, and Gut Microbiota Regulative Effects of Separated Hydrolysate of α-Lactalbumin on Potassium Oxonate- and Hypoxanthine-Induced Hyperuricemic Mice.

This study aims to investigate the anti-hyperuricemic and nephroprotective effects and the potential mechanisms of the separated gastrointestinal hydrolysates of α-lactalbumin on hyperuricemic mice. The gastrointestinal hydrolysate of α-lactalbumin, the hydrolysate fraction with molecular weight (MW) < 3 kDa (LH-3k), and the fragments with smallest MW among LH-3K harvested through dextran gel chromatography (F5) are used. Hyperuricemia mice are induced via daily oral gavage of potassium oxonate and hypoxanthine. F5 displays the highest in vitro xanthine oxidase (XO) inhibition among all the fractions separated from LH-3k. Oral administration of F5 significantly reduces the levels of serum uric acid (UA), creatinine, and urea nitrogen. F5 treatment could ameliorate kidney injury through alleviating oxidative stress and inflammation. F5 alleviates hyperuricemia in mice by inhibiting hepatic XO activity and regulating the expression of renal urate transporters. Gut microbiota analysis illustrates that F5 administration increases the abundance of some SCFAs producers, and inhibits the growth of hyperuricemia and inflammation associated genera. LH-3k exhibits similar effects but does not show significance as those of the F5 fraction. The anti-hyperuricemia and nephroprotective functions of F5 are mediated by inhibiting hepatic XO activity, ameliorating oxidative stress and inflammation, regulating renal urate transporters, and modulating the gut microbiota in hyperuricemic mice.

Zinc normalizes hepatic lipid handling via modulation of ADA/XO/UA pathway and caspase 3 signaling in highly active antiretroviral therapy-treated Wistar rats

BackgroundAlthough highly active antiretroviral therapy (HAART) is effective in the management of HIV, it has been reported to induce hepatic injury and non-alcoholic fatty liver (NAFLD). However, there is a lack of data on the roles of the adenosine deaminase (ADA)/xanthine oxidase (XO)/uric acid (UA) pathway and caspase 3 signaling in HAART-induced NAFLD. Also, whether or not zinc confers protection against HAART-induced NAFLD is not known. AimThis study evaluated the involvement of the ADA/XO/UA pathway and caspase 3 signaling in HAART-induced hepatic lipid accumulation. It also evaluated the possible protective effect of zinc in HAART-induced hepatic lipid accumulation and injury. MethodsThirty two male Wistar rats (n = 8/group) were assigned into four groups namely; vehicle-treated (p.o), zinc-treated (3 mg/kg/day of elemental zinc; p.o), HAART-treated (a cocktail of 52.9 mg/kg of Efavirenz, 26.48 mg/kg of Lamivudine, and 26.48 mg/kg of Tenofovir; p.o), and HAART + zinc-treated groups. The treatment lasted for 8 weeks. ResultsHAART administration led to increased body weight and hepatic weight, but unaltered hepatic organo-somatic index. HAART exposure also resulted in impaired glucose homeostasis, evidenced by increased fasting blood glucose, hyperinsulinemia, and insulin resistance (IR), increased plasma and hepatic cholesterol and triglycerides, and impaired hepatic function as depicted by elevated hepatic injury markers and reduced glycogen synthase activity and glycogen content. These findings were accompanied by increased plasma and hepatic ADA and XO activities, UA and malondialdehyde levels, inflammatory markers, and caspase 3 activities. However, HAART suppressed plasma and hepatic antioxidant defenses. Furthermore, HAART distorted hepatic histoarchitecture and reduced hepatic sinusoidal diameter. Co-administration of zinc with HAART normalized HAART-induced alterations. ConclusionsThese findings showed that downregulation of the ADA/XO/UA pathway and caspase 3 signalings may rescue the liver from HAART-induced lipid accumulation and injury.

Mild methylenetetrahydrofolate reductase deficiency accelerates liver triacylglycerol and uric acid accumulation in fructose-fed mice

A genetic predisposition to hepatic steatosis may be associated with dietary patterns. We hypothesized that a common variant in human methylenetetrahydrofolate reductase (MTHFR 677C→T) was previously associated with an increased risk of nonalcoholic fatty liver disease (NAFLD). In this study, we investigated the relationship between the human MTHFR polymorphism and NAFLD using fructose-fed male C57BL/6 Mthfr+/+ and Mthfr+/− mice, a model for the human gene variant. Mice were fed an 8% fructose solution for 12 weeks. Mthfr+/− mice had significantly increased abdominal fat mass and hepatic triglyceride (TG) but displayed a similar liver mass when compared with Mthfr+/+ mice. Liver morphology showed that mild MTHFR deficiency induced liver lipid droplet deposition and inflammatory cell infiltration, suggesting accelerated lipid accumulation in the liver. Moreover, mild MTHFR deficiency increased hepatic xanthine oxidase activity and uric acid accumulation. Using untargeted lipidomics, we identified 116 differentially expressed lipids species in the liver of Mthfr+/− mice when compared with Mthfr+/+ animals. The most significant lipid increase was observed in 47 TGs, followed by 33 phosphatidylcholines in Mthfr+/− mice liver. When compared with Mthfr+/+ liver, 9 TGs were dramatically decreased in Mthfr+/− liver. These changes were associated with upregulated gene expressions related to triglyceride synthesis and storage. Thus, Mthfr+/− mice developed NAFLD disease. These findings suggested the Mthfr variant may be at an increased risk of liver steatosis on a fructose solution diet.

Katsuwonus pelamis Peptide and its Complexes Protect Zebrafish and Mice From Hyperuricemia Through Promoting Kidney Excretion of Uric Acid and Inhibiting Liver Xanthine Oxidase Activity.

Katsuwonus pelamis peptide and its complexes have the effect of lowering uric acid (UA)-levels. To identify the effect and possible mechanisms, different concentrations of Katsuwonus pelamis peptide and its complexes were administered to the zebrafish and mice hyperuricemia models, and the UA level was measured. Meanwhile, the hyperuricemic mice were treated orally at 0.83, 1.67, and 5.00 mg/g body weight for 7 days with Katsuwonus pelamis peptide and the complexes groups, separately. The levels of serum UA (SUA), urinary UA (UUA), serum creatinine (SCR), blood urine nitrogen (BUN), and xanthine oxidase (XOD) activities were detected in each group. The results showed that the Katsuwonus pelamis peptide (125 μg/ml) and its complexes (83.3 and 250 μg/ml) effectively reduced UA level in zebrafish with hyperuricemia (p < 0.05). The Katsuwonus pelamis peptide at high concentration (5.00 mg/g) decreased the SUA level, SCR level, BUN level, and hepatic XOD activity, and the complexes (1.67 and 5.00 mg/g) significantly reduced the SUA level and hepatic XOD activity (p < 0.05) in the hyperuricemic mice. In addition, in a hyperuricemic mouse model, the UUA level was increased after treatment with Katsuwonus pelamis peptide and its complexes at high concentrations (p < 0.05). The total therapeutic effects in the Katsuwonus pelamis peptide complex group were better than those in the Katsuwonus pelamis peptide group. Thus, Katsuwonus pelamis peptide and its complexes may possibly be used to prevent hyperuricemia via promoting urate secretion and inhibiting XOD activity production.

Synergistic Impacts of Alpinia oxyphylla Seed Extract and Allopurinol against Experimental Hyperuricemia.

In traditional medicine, Alpinia oxyphylla Miquel seed has been used to treat gout and hyperuricemia-related symptoms by enhancing kidney functions. Allopurinol is the most commonly used drug to treat hyperuricemia; however, the drug has many adverse effects. Combining allopurinol with another compound could reduce the need for high doses and result in improved safety. We investigated the possible synergistic effects of Alpinia oxyphylla seed extract (AE) and allopurinol in decreasing urate concentrations in rats with potassium oxonate-induced hyperuricemia. This study evaluated the effects of allopurinol combined with AE on levels of serum urate, blood urea nitrogen (BUN), and creatinine in a hyperuricemic rat model. The effects of allopurinol plus AE on xanthine oxidase (XOD) activity and urate uptake were measured. The concomitant administration of allopurinol and AE normalized serum urate and reduced BUN and creatinine. The attenuation of hyperuricemia-induced impaired kidney function was related to downregulation of renal urate transporter 1 and upregulation of renal organic anion transporter 1, with inhibition of serum and hepatic XOD activities. The antihyperuricemic effects of allopurinol were enhanced when combined with AE. These results suggested that the combined use of allopurinol and AE may have clinical efficacy in treating hyperuricemia.

Anti-hyperuricemic and Anti-gout Effects of Olive Juice Freeze Dried Powder in Rats

To investigate the anti-hyperuricemic and anti-gout effects of olive juice freeze dried powder(Hidrox®12%) and its underlying mechanisms, a hyperuricemia rat model was established by intraperitoneal injection of potassium oxazinate and was given olive juice freeze dried powder administration. The levels of serum uric acid(UA), creatinine(CR) and urea nitrogen(BUN), serum and hepatic xanthine oxidase(XOD) activities, and the protein expression level of urate transporter 1(URAT1) in kidney were evaluated. Besides, a gout rat model induced by monosodium urate(MSU) was established to detect the effects of olive juice freeze dried powder on the paw swelling rate, and the level of TNF-α and IL-1β in serum. UPLC-ESI-MS/MS method was used to separate and identify the active ingredients for lowering UA. Results showed that, when compared with the model group, olive juice freeze dried powder（80 mg/kg） could significantly reduce the serum UA level(P<0.01) and reverse the elevated serum CR and BUN(P<0.01) levels caused by hyperuricemia. Further study revealed that the anti-hyperuricemic effect of olive juice freeze dried powder might be associated with its inhibition toward the serum and hepatic XOD activities and the downregulation of renal URAT1 expression. In the gouty model, olive juice freeze dried powder(80 mg/kg) significantly alleviated the joint swelling(P<0.001) caused by MSU and reduced the serum TNF-α and IL-1β levels respectively(P<0.05). Further study revealed that piperine and luteolin might be the active ingredients of olive juice freeze dried powder owing to their inhibitory activity on URAT1-mediated urate transport in vitro. In summary, olive juice freeze dried powder could alleviate hyperuricemia and acute gouty arthritis in vivo, the uric acid-lowering effect of which might be related to the inhibition of XOD activities and down-regulation of renal URAT1 expression as well as inhibiting inflammatory reactions.

Antihyperuricemic Effect of Green Alga Ulva lactuca Ulvan through Regulating Urate Transporters

A novel polysaccharide from Ulva lactuca (ULP) was purified using a Sepharose CL-4B column. Fourier transform infrared spectroscopy, high-performance liquid chromatography, and nuclear magnetic resonance spectroscopy were employed to analyze the structure of ULP. It consisted of rhamnose (Rha), glucuronic acid (GluA), galactose (Gal), and xylose (Xyl) at a molar ratio of 32.75:22.83:1.07:6.46 with the molecular weight of 2.24 × 105 Da. The four major glycosidic residues found in ULP were →2,3)-α-l-Rhap-(1→, →4)-β-d-GlcpA-(1→, →2,6)-β-d-Galp-(1→, and →4)-β-d-Xylp-(1→. The antihyperuricemic activity of ULP was exhibited by detecting related biochemical indexes, urate transporter gene expressions, renal histopathology, and intestinal microbiota shifts. ULP obviously decreased the levels of serum uric acid (UA), blood urea nitrogen, and creatinine, while inhibited serum and hepatic xanthine oxidase activities as well as improved renal injury in hyperuricemic mice. Furthermore, the upregulation of UA excretion genes ABCG2/OAT1 and downregulation of UA resorption genes URAT1 and GLUT9 were detected. In addition, ULP exerted its antihyperuricemic effect through regulating the intestinal microbiome, characterized by elevating the helpful microbial abundance, meanwhile declining the harmful bacterial abundance and restoring the gut microbiome homeostasis. This study demonstrates the antihyperuricemic activity of ULP and its potential effect for the treatment of hyperuricemia-related diseases.

Active components from Lagotis brachystachya maintain uric acid homeostasis by inhibiting renal TLR4-NLRP3 signaling in hyperuricemic mice.

Lagotis brachystachya Maxim is a herb widely used in traditional Tibetan medicine. Our previous study indicated that total extracts from Lagotis brachystachya could lower uric acid levels. This study aimed to further elucidate the active components (luteolin, luteoloside and apigenin) isolated from Lagotis brachystachya and the underlying mechanism in vitro and in vivo. The results showed that treatment with luteolin and luteoloside reversed the reduction of organic anion transporter 1 (OAT1) levels, while apigenin attenuated the elevation of urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) levels in uric acid-treated HK-2 cells, which was consistent with the finding in the kidneys of potassium oxonate (PO)-induced mice. On the other hand, hepatic xanthine oxidase activity was inhibited by the components. In addition, all of these active components improved the morphology of the kidney in hyperuricemic mice. Moreover, molecular docking showed that luteolin, luteoloside and apigenin could bind Toll-like receptor 4 (TLR4) and NLR family pyrin domain containing 3 (NLRP3). Congruently, western blot analysis showed that the components inhibited TLR4/myeloid differentiation primary response 88 (MyD88)/NLRP3 signaling. In conclusion, these results indicated that luteolin, luteoloside and apigenin could attenuate hyperuricemia by decreasing the production and increasing the excretion of uric acid, which were mediated by inhibiting inflammatory signaling pathways.

Lactic acid bacteria strains relieve hyperuricaemia by suppressing xanthine oxidase activity via a short-chain fatty acid-dependent mechanism.

Globally, the incidence of hyperuricaemia is steadily increasing. The evidence increasingly suggests an association between hyperuricaemia and the gut microbiota, which may enable the development of a novel therapeutic approach. We studied the effects of treatment with lactic acid bacteria (LAB) on hyperuricaemia and their potential underlying mechanisms. A mouse model of hyperuricaemia was generated by oral gavage with hypoxanthine and intraperitoneal injections of potassium oxonate for 2 weeks. The anti-hyperuricaemic activities of 10 LAB strains relative to allopurinol as a positive drug control were investigated in the mouse model. Lactobacillus rhamnosus R31, L. rhamnosus R28-1 and L. reuteri L20M3 effectively reduced the uric acid (UA) concentrations in serum and urine and the xanthine oxidase (XOD) activity levels in serum and hepatic tissue in mice with hyperuricaemia. These strains also reversed the elevated lipopolysaccharide (LPS) concentration, hepatic inflammation and slight renal injury associated with hyperuricaemia. A correlation analysis revealed that UA-reducing LAB strains promoted short-chain fatty acid (SCFA) production to suppress serum and hepatic XOD activity by increasing the abundances of SCFA production-related gut bacterial taxa. However, the UA-reducing effects of LAB strains might not be mediated by purine degradation. In summary, L. rhamnosus R31, L. rhamnosus R28-1 and L. reuteri L20M3 relieved hyperuricaemia in our mouse model by promoting SCFA production in a purine degradation-independent manner. Our findings suggest a novel therapeutic approach involving LAB strains for hyperuricaemia.

Sonneratia apetala seed oil attenuates potassium oxonate/hypoxanthine-induced hyperuricemia and renal injury in mice.

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.

Antihyperuricemic Effect of Urolithin A in Cultured Hepatocytes and Model Mice.

Hyperuricemia is defined as a disease with high uric acid (UA) levels in the blood and a strong risk factor for gout. Urolithin A (UroA) is a main microbial metabolite derived from ellagic acid (EA), which occurs in strawberries and pomegranates. In this study, we evaluated antihyperuricemic effect of UroA in both cultured hepatocytes and hyperuricemic model mice. In cultured hepatocytes, UroA significantly and dose-dependently reduced UA production. In model mice with purine bodies-induced hyperuricemia, oral administration of UroA significantly inhibited the increase in plasma UA levels and hepatic xanthine oxidase (XO) activity. In addition, DNA microarray results exhibited that UroA, as well as allopurinol, a strong XO inhibitor, induced downregulation of the expression of genes associated with hepatic purine metabolism. Thus, hypouricemic effect of UroA could be, at least partly, attributed to inhibition of purine metabolism and UA production by suppressing XO activity in the liver. These results indicate UroA possesses a potent antihyperuricemic effect and it could be a potential candidate for a molecule capable of preventing and improving hyperuricemia and gout.