Excessive dietary purine intake can lead to hyperuricemia, facilitating the precipitation and deposition of monosodium urate crystals in joints, which subsequently triggers inflammatory cascades leading to gout. Alcohol consumption exacerbates this condition by accelerating purine metabolism and impairing renal uric acid excretion, thereby further increasing serum uric acid concentrations and aggravating gout severity. In this study, Pediococcus pentosaceus SMM847 was screened based on its inosine degradation efficiency. Notably, the strain SMM847 also exhibited alcohol dehydrogenase and aldehyde dehydrogenase activities, as well as a substantial capability for ethanol degradation. In a hyperuricemic rat model, administration of SMM847 significantly reduced serum uric acid levels. Furthermore, in an ethanol-stressed mouse model, SMM847 markedly decreased blood ethanol concentrations, restored hepatic metabolic function, and enhanced endogenous antioxidant capacity, thereby counteracting ethanol-induced disturbances in nutrient absorption and systemic metabolism. Importantly, SMM847 showed no hepatotoxicity and effectively mitigated alcohol-induced histopathological liver injury. By concurrently targeting hyperuricemia and acute alcohol intoxication, this study identifies SMM847 as a promising probiotic candidate for the management of gout and alcohol-related metabolic disorders.

Gout is a chronic inflammatory disease driven by hyperuricemia and recurrent immune activation. However, gout may occur in the absence of elevated serum uric acid levels, which complicates clinical diagnosis and highlights the need for reliable molecular biomarkers. The molecular mechanisms underlying gout progression remain incompletely understood. This observational study integrated bioinformatics analyses with experimental validation. Publicly available transcriptomic datasets were analyzed to identify differentially expressed genes between gout patients and healthy controls. Functional enrichment analysis, protein-protein interaction network construction, immune cell infiltration analysis, competing endogenous RNA network analysis, and gene set enrichment analysis were performed to explore C-X-C motif chemokine ligand 8 (CXCL8)-associated molecular pathways. In vitro experiments were conducted to evaluate hyperuricemia-induced inflammatory responses in renal cells. A total of 1848 differentially expressed genes were identified, which were predominantly enriched in immune and inflammatory regulatory pathways. Five hub genes were highlighted, among which CXCL8 emerged as a key mediator of immune cell activation. Gene set enrichment analysis revealed that CXCL8 was significantly associated with inflammatory signaling pathways, including the NOD-like receptor signaling pathway. Potential upstream regulators of CXCL8 were also identified. Experimental validation demonstrated that elevated uric acid levels induced renal cell injury and inflammatory responses, accompanied by increased CXCL8 expression and activation of the NOD-like receptor family pyrin domain containing 3 inflammasome pathway. This study preliminarily identifies CXCL8 as a critical inflammatory mediator involved in gout progression and suggests its potential value as a molecular biomarker and therapeutic target, providing a basis for future diagnostic and therapeutic strategies.

Sequence-specific gene knockdown technologies are crucial for fundamental research and therapeutic applications. RNA interference and CRISPR interference, while extensively utilized for gene expression manipulation, face limitations due to their ectopic or transient expression. In this study, we developed a generalizable and efficient method to downregulate gene expression in human 293T cells by introducing de novo upstream ATGs (uATGs) of genes using CRISPR-Cas9-mediated genome editing. Through CRISPR library screening, in-depth sequencing, and flow cytometry analysis, we validated that the introduction of uATGs served as an effective method to suppress protein expression. Our findings further revealed that this strategy can be tailored to diminish endogenous gene expression in tumor cells without affecting the mRNA transcription levels. Importantly, by introducing a uATG into the 5' untranslated region (UTR) of the Uox gene, we successfully established a Uox-knockdown (KD) mouse model of hyperuricemia associated with metabolic disorders. This model demonstrated hyperuricemia, with serum uric acid levels that exceeded 400 µmol L[-1], along with renal dysfunction, as indicated by elevated serum creatinine and blood urea nitrogen levels. Examination of the kidneys from 8-week-old Uox-KD mice revealed abnormal histopathological characteristics, including partial dilation of Bowman's capsules and renal tubules, focal nephron collapse and necrosis, and lymphocytic infiltration. In addition, the mice exhibited lipid and glucose metabolism disorders, all while maintaining a normal lifespan. This spontaneous hyperuricemia model has potential as a valuable tool for long-term studies on hyperuricemia and gout. Taken together, we present an efficient approach for the constant suppression of specific gene expression in mammalian cells and the development of a Uox-KD mouse model of hyperuricemia via CRISPR-Cas9-mediated uATG introduction. This offers broad implications for fundamental research and therapeutic applications.

This study aimed to investigate the ameliorative effect of hyperbaric oxygen (HBO) on a rat model of hyperuricemia induced by combined drugs and its underlying mechanism. A rat model of drug-induced hyperuricemia (HUA)was established by using a combination of yeast, potassium oxonate (PO) and hypoxanthine (Hx). During the modeling process, hyperbaric oxygen therapy was also administered. Serum uric acid (UA), creatinine (Cr)and blood urea nitrogen (BUN)levels were measured, and HE staining was used to evaluate the histopathological damage of small intestine and kidney tissues. Serum non-targeted metabolomics analysis was conducted, and 16 S rRNA gene sequencing was used to analyze the changes in intestinal flora structure, to evaluate the therapeutic effect of hyperbaric oxygen therapy. The results showed that HBO therapy could significantly reduce the UA, Cr and BUN levels and alleviate the histopathological damage of small intestine and kidney tissues in model rats. At the same time, HBO therapy could regulate the imbalance of intestinal flora, reduce potential pathogenic bacteria, and reduce the endogenous production of UA by decreasing the relative abundance of Bacteroides and Alistipes. Further serum metabolomics analysis indicated that HBO therapy could improve the differential metabolites in HUA rats, and the pathways of these differential metabolites were mainly related to glutathione metabolism, as well as d-glutamine and d-glutamate metabolism. HBO therapy could regulate key pathways such as purine metabolism and amino acid metabolism, and promote the generation of UA excretion-related metabolites. This study confirmed that HBO could improve combined drug-induced HUA by remodeling the intestinal flora structure and regulating the host metabolic pathways, providing new experimental evidence and potential targets for non-pharmacological treatment of HUA.

Hyperuricemia refers to elevated levels of serum uric acid (SUA) beyond the normal physiological range in men and women. It is caused by increased endogenous synthesis, decreased renal clearance, or a combination. While hyperuricemia has long been associated with gout, new evidence suggests that it is a significant risk factor in the pathophysiology of a variety of cardiovascular and metabolic disorders, including hypertension, metabolic syndrome, coronary artery disease, heart failure, type 2 diabetes mellitus, and chronic kidney disease. The increasing global frequency of hyperuricemia has sparked scientific and clinical interest in the possible mechanistic relationship between elevated SUA levels and cardiovascular morbidity. Hyperuricemia's pathological mechanisms, including oxidative stress, endothelial dysfunction, and systemic inflammation, may lead to vascular remodeling, atherosclerotic plaque progression, and increased cardiovascular mortality. This case report emphasizes the need for increased clinical awareness of the cardiovascular dangers associated with asymptomatic hyperuricemia. Its purpose is to investigate the potential link between elevated SUA and the severity of coronary artery involvement, emphasizing the importance of early detection and treatment of hyperuricemia as a modifiable cardiovascular risk factor.

Gout is a common autoinflammatory disease that clinically manifests as recurrent joint redness, swelling, and pain, but the molecular mechanism of recurrent gouty inflammation remains unclear. Circular RNAs (circRNAs) might exert their function by regulating autophagy. Our previous studies revealed that autophagy-related genes (ATGs) are differentially expressed in patients with acute gout. The aim of this study was to investigate the molecular mechanism by which circ_0058051 regulates autophagy as a competitive endogenous RNA (ceRNA) in recurrent gouty inflammation. Real-time quantitative PCR was used to measure the expression of circ_0058051, miR-129-5p, ATG7, LC3, and IL-1β. Western blotting was used to assess the protein levels of ATG7, LC3, and IL-1β. Enzyme-linked immunosorbent assay (ELISA) was used to measure the IL-1β, IL-6, and TNF-α levels. A dual-luciferase reporter assay was used to confirm the interaction between circ_0058051, miR-129-5p, and ATG7. The gout group expressed significantly more circ_0058051 and ATG7 and significantly less miR-129-5p than the HC group. In the 20 paired cases, compared with stable gout cases, the expression of circ_0058051 and ATG7 was significantly greater during a gout attack and even greater in patients with gout recurrence. The significant decrease in miR-129-5p expression was more pronounced in patients with gout recurrence. In the simulation model of gout recurrence in the peripheral blood of intercritical gout patients stimulated with MSU, circ_0058051 peaked 2 h after MSU stimulation, ATG7 peaked 1 h after MSU stimulation, and miR-129-5p expression was lowest 1 h after MSU stimulation. In addition, the expression levels of circ_0058051, ATG7, IL-1β, TNF-α, IL-6, and LC3 significantly increased after THP-1 macrophages were treated with MSU, and the expression of miR-129-5p significantly decreased. In MSU-stimulated THP-1 macrophages, circ_0058051 sponges miR-129-5p to promote the expression of the miR-129-5p target gene ATG7, leading to acute gout attack. Our findings suggest that circ_0058051 is involved in the recurrence of acute gout by targeting miR-129-5p to regulate ATG7-mediated autophagy.

Hyperuricemia has become a public threat to human health, and conventional medical treatment only aims to inhibit xanthine oxidase (XOD). Endogenous purine biosynthesis and purinosome formation are neglected in research of medical mechanism. In this study, the therapeutic effect and mechanism of metformin was explored in chronic high-fructose-induced hyperuricemic rats. Results indicated that four weeks of metformin administration effectively reduced uric acid (UA), creatinine, and urea levels, ameliorated renal and hepatic injuries, and promoted glycogen synthesis in hyperuricemic rats. Furthermore, metformin remarkedly downregulated the mRNA and protein expression of core enzymes in pentose phosphate pathway (PPP), and de novo purine biosynthesis (DNPB) of endogenous purine. Metformin was found to markedly inhibit the purine salvage pathway (PSP) and XOD to retard purine recycling and metabolism. Additionally, metformin effectively restored physiological purinosome architecture, preventing aberrant enzyme clustering and subcellular redistribution. The hepatic levels of IMP, inosine, hypoxanthine and xanthine in hyperuricemic rats were remarkably decreased by metformin. Besides, metformin favorably maintained the gut microbiome homeostasis and normalized purine metabolism to lower purine levels in intestine. Taken together, the results for the first time indicated that metformin exerted appreciable anti-hyperuricemic effect, at least partly, via inhibiting original biosynthetic and metabolic pathways of endogenous purine simultaneously mediated by PPP/DNPB/XOD, purinosome assembly, and modulating gut microflora profile. This work provided a scientific basis for its potential application in hyperuricemia therapy beyond its classical use in diabetes.

ELABELA (ELA), an endogenous peptide, exhibits antioxidant and anti-inflammatory properties in the heart and kidney. This study aimed to explore the therapeutic potential of ELA in hyperuricemia (HUA) and its underlying mechanism. Male C57BL/6 mice were used to induce HUA via oral administration of adenine and potassium oxonate for 14 days. 32 or 11 amino-acid ELA peptides (ELA32 or ELA11) were intraperitoneally injected into HUA mice. Compared with the HUA group, both ELA peptides significantly reduced serum UA levels, as well as hepatic expression and activity of XOD. ELA32 also decreased BUN, serum creatinine, AST, ALT and cholesterol levels while ELA11 diminished BUN and serum creatinine. Furthermore, both ELA peptides modulated bile acid (BA) synthesis, primarily through suppression of CYP27A1. Hepatic BA profiling revealed that HUA increased levels of taurochenodeoxycholic acid (TCDCA), whereas ELA treatment elevated levels of taurocholic acid (TCA), tauroursodeoxycholic acid (TUDCA), and tauro-β-muricholic acid (T-βMCA). ELA32 additionally promoted accumulation of cholic acid (CA) and taurodeoxycholic acid (TDCA). In human hepatocytes HepG2, both ELA peptides reduced H2O2-induced protein levels of XOD and CYP27A1, while enhanced FXR expression. CYP27A1 deficiency mimicked the effects of ELA32 on XOD and FXR expression under H2O2 stimulation. Moreover, TCA, TUDCA, TCDCA, CA and TDCA reversed H2O2-mediated regulation of XOD and FXR expression. These findings suggest that both ELA32 and ELA11 alleviate HUA in mice primarily by inhibiting XOD expression through CYP27A1-regulated BA metabolism. Our study suggests that ELA has therapeutic potential for the treatment of HUA.

Phellodendri Chinensis Cortex, a time-honored Chinese materia medica, has long been applied in the management of gout and other diseases. Hyperuricemia (HUA) is the vital contributor for the occurrence and progression of gout. Oxyberberine (OBB), an oxidized protoberberine alkaloid, is naturally present in Phellodendri Chinensis Cortex. The work made a pioneering endeavor to unravel the potential anti-HUA effect and mechanism of OBB. Hight fructose-induced experimental HUA in rats was employed. Results indicated that OBB significantly reduced the body weight and UA level, and concurrently mitigated hepatic injury, which achieved superior therapeutic effect to its prodrug berberine (BBR). OBB treatment remarkably alleviated inflammatory response and oxidative stress. Furthermore, OBB appreciably activated the gene expression of key enzymes involved in the pentose phosphate pathway (PPP), and inhibited the transcriptional or translational expression of key enzymes in de novo purine biosynthesis (DNPB), as well as modulated purine salvage pathway (PSP), collectively leading to a reduction in UA level. Molecular docking and dynamic simulation further confirmed the dynamic stability of OBB-target protein complexes. Meanwhile, OBB favorably modulated the fructose-induced gut dysbiosis, enhanced the abundance of probiotics and abated detrimental counterparts, which were associated with promoting UA catabolism and inhibiting inflammation response via correlation analysis. In summary, our findings in pioneering endeavor found that OBB efficaciously ameliorated fructose-elicited HUA. The mechanism was intimately associated with alleviating endogenous purine original biosynthetic and metabolic pathways and favorably harmonizing gut microflora homeostatic disequilibrium. This study has uncovered innovative mechanisms underlying OBB's therapeutic potential for HUA and bolstered the scientific basis for the historical use of Phellodendri Chinensis Cortex and BBR in the management of HUA.

Trained immunity (TRIM) is the process through which the innate immune system undergoes memory-like epigenetic and metabolic reprogramming following an earlier infectious challenge. Trained immunity can be induced, in a similar fashion to microbial structures, by various endogenous compounds: oxidized low-density lipoproteins, lipoprotein(a), glucose and uric acid, and monosodium urate. Lipids, glucose, and protein metabolic dysfunction have the potential to perpetuate a proinflammatory feedback loop through the induction of maladaptive trained immunity programs, as shown in cardiovascular diseases, diabetes, and hyperuricemia. Molecular mechanisms leading to TRIM are susceptible to homeostatic disruptions of advanced age, and maladaptive TRIM may be the link between immune aging and age-associated pathologies. The present review discusses the current knowledge on metabolic pathways in adaptive and maladaptive trained immunity and its deleterious consequences of inappropriate activation during aging. Finally, we discuss how several dietary patterns modulate immunometabolism and influence trained immunity in aging.

Fructose is a nutrient used widely and indiscriminately as a sweetener in various types of foods and beverages. Accumulating evidence suggests that dietary fructose has a close relationship with metabolic diseases like hyperuricemia (HUA). However, the role and metabolic fate of fructose intake remain elusively obscure. The present work made a pioneering endeavor to unravel the potential mechanistic link between prolonged fructose overconsumption and the incidence of HUA. High-fructose (30%) free drinking was provided to rats for 17 weeks. Results indicated that long-term high-fructose intake remarkably increased the levels of uric acid, creatinine, and urea. Besides, mild renal alteration induced by high fructose was observed in the hyperuricemic rats. Instead of activating ketohexokinase, high-fructose intake activated the pentose phosphate pathway (PPP) to produce abundant ribose 5-phosphate and phosphoribosyl pyrophosphate. The de novo purine biosynthesis (DNPB) was activated to produce purines and accelerate the purine cycle. High-fructose intake significantly enhanced the expression of core enzymes of DNPB and changed the purinosome formation and forming areas. Furthermore, up-regulation of xanthine oxidase (XOD) promoted the purine metabolism, resulting in increased levels of inosine monophosphate, inosine, hypoxanthine, and xanthine. Besides, the targeted metabolome analysis also showed that fructose metabolism triggered bioenergetic alteration with the consumption of ATP and a surge in NAD[+] and NADH. Hence, chronic ingestion of high-fructose contributed to HUA, which was intimately associated with activation of original biosynthetic and metabolic pathways of endogenous purine simultaneously mediated by PPP, DNPB, and XOD and accompanied by bioenergetic alteration.

Protein S-nitrosylation (SNO), a redox-based posttranslational modification of cysteine thiols, plays a crucial role in various signaling pathways. Peroxiredoxin 2 (PRDX2) is one of the most potent ROS scavenging proteins, providing protection against oxidative stress damage, with its function regulated by SNO. However, the precise role of SNO-PRDX2 in hyperuricemic nephropathy remains poorly understood. In this study, we identified PRDX2 as a highly S-nitrosylated target in hyperuricemic nephropathy using a biotin switch assay. The elevation of SNO-PRDX2 was observed in kidneys of hyperuricemic mice as well as in uric acid (UA)-treated human renal tubular epithelial (HK-2) cells. S-nitrosoglutathione (GSNO), an endogenous nitric oxide carrier, induced SNO modification of PRDX2, promoting mitochondrial dysfunction, oxidative stress, and cell apoptosis in HK-2 cells. Transfection with a plasmid containing a mutated cysteine 172 (Cys172) of PRDX2 yielded a decrease in SNO-PRDX2 levels in both hyperuricemic mice and UA-cultured HK-2 cells. Furthermore, administration of adeno-associated viruses carrying the Cys172-mutated PRDX2 significantly ameliorated renal interstitial fibrosis and reduced mitochondrial dysfunction, oxidative stress, and cell apoptosis in HUA-treated mice. In conclusion, our findings indicate that SNO modification of PRDX2 at Cys172 mediates HUA-induced kidney interstitial fibrosis, suggesting that SNO-PRDX2 may serve as a potential therapeutic target for HUA-induced renal injury.

Hydrogen sulfide (H2S) is an important gasotransmitter that regulates a wide range of pathophysiological processes. Higher uric acid levels are associated with an increased risk of metabolic diseases. The causal mechanism linking H2S signalling and uric acid metabolism in skeletal muscles has not yet been elucidated. This study aimed to explore the intertwined metabolisms of H2S and uric acid as well as their integrated roles in controlling myoblast cell functions. It was first found that purine overload increased uric acid levels, promoted oxidative stress, mitochondrial damage, and apoptosis in cultured mouse myoblasts, which could be reversed by the exogenously application of H2S at physiologically relevant concentration. In addition, H2S significantly inhibited the expressions of inflammatory genes (encoding IL2, IL4, and TNFα) but had no effect on oxidative stress, mitochondrial damage and cell death induced by excessive uric acid. Mechanistically, H2S inhibited xanthine oxidoreductase (XOR) activity by blocking the conversion of xanthine dehydrogenase (XDH) to xanthine oxidase (XO), thus reducing uric acid levels and improving myoblast functions. In addition, purine and uric acid attenuated the expression of cystathionine gamma-lyase (CSE, an H2S-generating enzyme) and suppressed endogenous H2S production. Blood uric acid levels and skeletal muscle XOR activity were significantly higher in CSE knockout mice than in wild-type mice. This study revealed a mutual interaction between H2S signalling and uric acid metabolism in the regulation myoblast functions. Thus, the CSE/H2S system may be a target for the prevention of hyperuricemia-related metabolic syndromes.

Hyperuricemia (HUA) refers to the presence of excess uric acid (UA) in the blood, which increases the risk of chronic kidney disease and gout. Probiotics have the potential to alleviate HUA.