WWC1 upregulation accelerates hyperuricemia by reduction in renal uric acid excretion through Hippo signaling pathway.

Hyperuricemia (HUA) is a metabolic disorder characterized by elevated serum uric acid (UA), primarily attributed to the hepatic overproduction and renal underexcretion of UA. Despite the elucidation of molecular pathways associated with this underexcretion, the etiology of HUA remains largely unknown. In our study, using by Uox knockout rats, HUA mouse, and cell line models, we discovered that the increased WWC1 levels were associated with decreased renal UA excretion. Additionally, using knockdown and overexpression approaches, we found that WWC1 inhibited UA excretion in renal tubular epithelial cells. Mechanistically, WWC1 activated the Hippo pathway, leading to phosphorylation and subsequent degradation of the downstream transcription factor YAP1, thereby impairing the ABCG2 and OAT3 expression through transcriptional regulation. Consequently, this reduction led to a decrease in UA excretion in renal tubular epithelial cells. In conclusion, our study has elucidated the role of upregulated WWC1 in renal tubular epithelial cells inhibiting the excretion of UA in the kidneys and causing HUA.

Current updates for hyperuricemia and gout in age-related macular degeneration.

The escalating prevalence of metabolic syndrome poses a significant public health challenge, particularly among aging populations, with metabolic dysfunctions contributing to pro-inflammatory states. In this review, we delved into the less recognized association between hyperuricemia (HUA), a manifestation of metabolic syndrome and a primary risk factor for gout, and age-related macular degeneration (AMD), a sight-threatening ailment predominantly affecting the elderly. In recent years, inflammation, particularly its involvement in complement pathway dysregulation, has gained prominence in AMD pathophysiology. The contradictory role of uric acid (UA) in intercellular and intracellular environments was discussed, highlighting its antioxidant properties in plasma and its pro-oxidant effects intracellularly. Emerging evidence suggests a potential link between elevated serum uric acid levels and choroid neovascularization in AMD, providing insights into the role of HUA in retinal pathologies. Various pathways, including crystal-induced and non-crystal-induced mechanisms, were proposed to indicate the need for further research into the precise molecular interactions. The implication of HUA in AMD underscores its potential involvement in retinal pathologies, which entails interdisciplinary collaboration for a comprehensive understanding of its impact on retina and related clinical manifestations.

Lipidomics and metabolomics investigation into the effect of DAG dietary intervention on hyperuricemia in athletes.

The occurrence of hyperuricemia (HUA; elevated serum uric acid) in athletes is relatively high despite that exercise can potentially reduce the risk of developing this condition. Although recent studies have shown the beneficial properties of DAG in improving overall metabolic profiles, a comprehensive understanding of the effect of DAG in modulating HUA in athletes is still lacking. In this study, we leveraged combinatorial lipidomics and metabolomics to investigate the effect of replacing TAG with DAG in the diet of athletes with HUA. A total of 1,074 lipids and metabolites from 94 classes were quantitated in serum from 33 athletes, who were categorized into responders and non-responders based on whether serum uric acid levels returned to healthy levels after the DAG diet intervention. Lipidomics and metabolomics analyses revealed lower levels of xanthine and uric acid in responders, accompanied by elevated plasmalogen phosphatidylcholines and diminished acylcarnitine levels. Our results highlighted the mechanisms behind how the DAG diet circumvented the risk and effects associated with high uric acid via lowered triglycerides at baseline influencing the absorption of DAG resulting in a decline in ROS and uric acid production, increased phospholipid levels associated with reduced p-Cresol metabolism potentially impacting on intestinal excretion of uric acid as well as improved ammonia recycling contributing to decreased serum uric acid levels in responders. These observed alterations might be suggestive that successful implementation of the DAG diet can potentially minimize the likelihood of a potentially vicious cycle occurring in high uric acid, elevated ROS, and impaired mitochondrial metabolism environment.

Quantified Metabolomics and Lipidomics Profiles Reveal Serum Metabolic Alterations and Distinguished Metabolites of Seven Chronic Metabolic Diseases.

The co-occurrence of multiple chronic metabolic diseases is highly prevalent, posing a huge health threat. Clarifying the metabolic associations between them, as well as identifying metabolites which allow discrimination between diseases, will provide new biological insights into their co-occurrence. Herein, we utilized targeted serum metabolomics and lipidomics covering over 700 metabolites to characterize metabolic alterations and associations related to seven chronic metabolic diseases (obesity, hypertension, hyperuricemia, hyperglycemia, hypercholesterolemia, hypertriglyceridemia, fatty liver) from 1626 participants. We identified 454 metabolites were shared among at least two chronic metabolic diseases, accounting for 73.3% of all 619 significant metabolite-disease associations. We found amino acids, lactic acid, 2-hydroxybutyric acid, triacylglycerols (TGs), and diacylglycerols (DGs) showed connectivity across multiple chronic metabolic diseases. Many carnitines were specifically associated with hyperuricemia. The hypercholesterolemia group showed obvious lipid metabolism disorder. Using logistic regression models, we further identified distinguished metabolites of seven chronic metabolic diseases, which exhibited satisfactory area under curve (AUC) values ranging from 0.848 to 1 in discovery and validation sets. Overall, quantitative metabolome and lipidome data sets revealed widespread and interconnected metabolic disorders among seven chronic metabolic diseases. The distinguished metabolites are useful for diagnosing chronic metabolic diseases and provide a reference value for further clinical intervention and management based on metabolomics strategy.

Uric acid-lowering effect of harpagoside and its protective effect against hyperuricemia-induced renal injury in mice.

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-1ß in the kidney. Harp was a promising anti-HUA agent.

Soluble urate-induced effects on cytokine production in vitro - Assessment of methodologies and cell types.

BACKGROUND: Hyperuricemia has been shown to be an inducer of pro-inflammatory mediators by human primary monocytes. To study the deleterious effects of hyperuricemia, a reliable and stable in vitro model using soluble urate is needed. One recent report showed different urate-dissolving methods resulted in either pro-inflammatory or anti-inflammatory properties. The aim of this study was to compare the effect of two methods of dissolving urate on both primary human peripheral blood mononuclear cells (PBMCs) and THP-1 cells. The two methods tested were 'pre-warming' and 'dissolving with NaOH'. METHODS: Primary human PBMCs and THP-1 cells were exposed to urate solutions, prepared using the two methodologies: pre-warming and dissolving with NaOH. Afterwards, cells were stimulated with various stimuli, followed by the measurement of the inflammatory mediators IL-1ß, IL-6, IL-1Ra, TNF, IL-8, and MCP-1. RESULTS: In PBMCs, we observed an overall pro-inflammatory effect of urate, both in the pre-warming and the NaOH dissolving method. A similar pro-inflammatory effect was seen in THP-1 cells for both dissolving methods after restimulation. However, THP-1 cells exhibited pro-inflammatory profile with exposure to urate alone without restimulation. We did not find MSU crystals in our cellular assays. CONCLUSIONS: Overall, the urate dissolving methods do not have critical impact on its inflammatory properties. Soluble urate prepared using either of the two methods showed mostly pro-inflammatory effects on human primary PBMCs and monocytic cell line THP-1. However, human primary PBMCs and the THP-1 differ in their response to soluble urate without restimulation.

Intermittent high altitude hypoxia induced liver and kidney injury leading to hyperuricemia.

About 140 million people worldwide live at an altitude above 2500 m. Studies have showed an increase of the incidence of hyperuricemia among plateau populations, but little is known about the possible mechanisms. This study aims to assess the effects of high altitude on hyperuricemia and explore the corresponding mechanisms at the histological, inflammatory and molecular levels. This study finds that intermittent hypobaric hypoxia (IHH) exposure results in an increase of serum uric acid level and a decrease of uric acid clearance rate. Compared with the control group, the IHH group shows significant increases in hemoglobin concentration (HGB) and red blood cell counts (RBC), indicating that high altitude hyperuricemia is associated with polycythemia. This study also shows that IHH exposure induces oxidative stress, which causes the injury of liver and renal structures and functions. Additionally, altered expressions of organic anion transporter 1 (OAT1) and organic cation transporter 1 (OCT1) of kidney have been detected in the IHH exposed rats. The adenosine deaminase (ADA) expression levels and the xanthione oxidase (XOD) and ADA activity of liver of the IHH exposure group have significantly increased compared with those of the control group. Furthermore, the spleen coefficients, IL-2, IL-1ß and IL-8, have seen significant increases among the IHH exposure group. TLR/MyD88/NF-κB pathway is activated in the process of IHH induced inflammatory response in joints. Importantly, these results jointly show that IHH exposure causes hyperuricemia. IHH induced oxidative stress along with liver and kidney injury, unusual expression of the uric acid synthesis/excretion regulator and inflammatory response, thus suggesting a potential mechanism underlying IHH-induced hyperuricemia.

Hyperuricemia: A key contributor to endothelial dysfunction in cardiovascular diseases.

As an end product of purine metabolism, uric acid (UA) is a major endogenous antioxidant in humans. However, impaired UA synthesis and excretion can lead to hyperuricemia (HUA), which may in turn induce endothelial dysfunction (ED) and contribute to the pathogenesis of cardiovascular diseases (CVDs; e.g., atherosclerosis and hypertension). In this review, we discuss recent advances and novel insights into the effects exerted by HUA conditions in ED and related underlying mechanisms focusing on impaired UA metabolism, reduction in the synthesis and bioavailability of nitric oxide, endothelial cell injury, the endothelial-to-mesenchymal transition, insulin resistance, procoagulant activity, and acquisition of an inflammatory phenotype. We additionally discuss intervention strategies for HUA-induced ED and the paradoxical roles of UA in endothelial function. We summarize major conclusions and perspectives: the deleterious effects of HUA contribute to the initiation and progression of CVD-related ED. However, the treatment strategies (in addition to urate-lowering therapy) for increasing endothelial function are limited because the majority of literature on pharmacological and pathophysiological mechanisms underlying HUA-induced ED solely describes in vitro models. Therefore, a better understanding of the mechanisms involved in HUA-induced ED is critical to the development of novel therapies for preventing and treating CVD-HUA comorbidities.

The anti-hyperuricemic and gut microbiota regulatory effects of a novel purine assimilatory strain, Lactiplantibacillus plantarum X7022.

PURPOSE: Probiotics have been reported to effectively alleviate hyperuricemia and regulate the gut microbiota. The aim of this work was to study the in vivo anti-hyperuricemic properties and the mechanism of a novel strain, Lactiplantibacillus plantarum X7022. METHODS: Purine content and mRNA expression of purine assimilation related enzymes were determined by HPLC and qPCR, respectively. Hyperuricemic mice were induced by potassium oxonate and hypoxanthine. Uric acid (UA), blood urea nitrogen, creatinine and renal inflammation were examined by kits. The expression of renal UA transporters was subjected to western blotting. Kidney tissues were sectioned for histological analysis. The fecal short-chain fatty acids (SCFAs) were determined by HPLC, and gut microbiota was investigated using the 16S rDNA metagenomic sequencing. RESULTS: L. plantarum X7022 possesses a complete purine assimilation pathway and can exhaust xanthine, guanine, and adenine by 82.1%, 33.1%, and 12.6%, respectively. The strain exhibited gastrointestinal viability as 44% at the dose of 109 CFU/mL in mice. After four-week administration of the strain, a significant decrease of 35.5% in the serum UA level in hyperuricemic mice was achieved. The diminished contents of fecal propionate and butyrate were dramatically boosted. The treatment also alleviated renal inflammation and restored renal damage. The above physiological changes may due to the inhibited xanthine oxidase (XO) activity, as well as the expressional regulation of UA transporters (GLUT9, URAT1 and OAT1) to the normal level. Notably, gut microbiota dysbiosis in hyperuricemic mice was improved with the inflammation and hyperuricemia related flora depressed, and SCFAs production related flora promoted. CONCLUSION: The strain is a promising probiotic strain for ameliorating hyperuricemia.

Effect and mechanism of Yiqing decoction on hyperuricemia rats.

This study aimed to experimentally compare the uric acid-lowering effect and renal protection of Yiqing Fang in a rat model of hyperuricemia. Additionally, we used network pharmacology to predict the potential active components, targets, and pathways of Yiqing Fang. Male SD rats were randomly divided into control, model, Yiqing Fang, allopurinol, and probenecid groups. Serum creatinine (Scr), blood urea nitrogen (BUN), serum uric acid (UA), alanine transaminase (ALT), complete blood count, and urinary NAG enzyme levels were measured. Standard pathology and electron microscopy samples were prepared from the left kidney to observe renal pathological changes, renal fibrosis, and collagen III expression levels. In addition, we employed network pharmacology to investigate the molecular mechanisms and pathways of Yiqing Fang. The Yiqing Fang group showed significantly lower levels of Scr, BUN, UA, ALT, urinary NAG enzyme, complete blood count, and liver function tests compared to the model group (P < 0.05). Furthermore, both the Yiqing Fang and allopurinol groups exhibited significant reductions in renal pathological changes compared to the model group, along with decreased expression of collagen III. Network pharmacology analysis identified a total of 27 specific sites related to hyperuricemia. The main active components were predicted to include quercetin, berberine, beta-sitosterol, epimedin C, and dioscin. The primary target sites were predicted to include TNF, IL-6, IL-17, IL-1B, and VEGFA. Yiqing Fang may exert its effects through regulation of drug response, urate metabolism, purine compound absorption, inflammation response, lipopolysaccharide response, cytokine activity, and antioxidant activity. These effects may be mediated through signaling pathways such as IL-17, HIF-1, and AGE-RAGE. Yiqing Fang offers potential as a treatment for hyperuricemia due to its multiple active components, targeting of various sites, and engagement of multiple pathways.

Metabolomics of human umbilical vein endothelial cell-based analysis of the relationship between hyperuricemia and dyslipidemia.

BACKGROUND AND AIMS: Hyperuricemia frequently accompanies dyslipidemia, yet the precise mechanism remains elusive. Leveraging cellular metabolomics analyses, this research probes the potential mechanisms wherein hyperuricemia provokes endothelial cell abnormalities, inducing disordered bile metabolism and resultant lipid anomalies. METHODS AND RESULTS: We aimed to identify the differential metabolite associated with lipid metabolism through adopting metabolomics approach, and thereafter adequately validating its protective function on HUVECs by using diverse assays to measure cellular viability, reactive oxygen species, migration potential, apoptosis and gene and protein levels of inflammatory factors. Taurochenodeoxycholic acid (TCDCA) (the differential metabolite of HUVECs) and the TCDCA-involved primary bile acid synthesis pathway were found to be negatively correlated with high UA levels based on the results of metabolomics analysis. It was noted that compared to the outcomes observed in UA-treated HUVECs, TCDCA could protect against UA-induced cellular damage and oxidative stress, increase proliferation as well as migration, and decreases apoptosis. In addition, it was observed that TCDCA might protect HUVECs by inhibiting UA-induced p38 mitogen-activated protein kinase/nuclear factor kappa-B p65 (p38MAPK/NF-κB p65) pathway gene and protein levels, as well as the levels of downstream inflammatory factors. CONCLUSION: The pathogenesis of hyperuricemia accompanying dyslipidemia may involve high uric acid levels eliciting inflammatory reactions and cellular damage in human umbilical vein endothelial cells (HUVECs), mediated through the p38MAPK/NF-κB signaling pathway, subsequently impinging on cellular bile acid synthesis and reducing bile acid production.

Uric acid mediates kidney tubular inflammation through the LDHA/ROS/NLRP3 pathway.

PURPOSE: Hyperuricemia (HUA) is an important factor leading to chronic kidney disease (CKD). The kidney tubular inflammatory response is activated in HUA. This study aimed to investigate whether lactate dehydrogenase A (LDHA) is involved in mediating uric acid-induced kidney tubular inflammatory response. METHODS: In vivo, an HUA mouse model was established by continuous intraperitoneal injection of potassium oxonate (PO) for one week. A total of 18 C57BL/6J male adult mice were divided into three groups: control group, HUA group, and HUA+oxamate group, with six mice in each group. Oxamate was intraperitoneally injected into the mice one hour after PO injection. In vitro, an HUA model was simulated by stimulating HK-2 cells with uric acid. Oxamate and tempol inhibited LDHA and reactive oxygen species (ROS) in HK-2 cells. RESULTS: In HUA mice, blood uric acid levels were significantly elevated. LDHA in kidney tubular cells was significantly increased in both in vivo and in vitro HUA models, accompanied by an increase in kidney tubular inflammation and ROS. Mechanistically, LDHA mediates uric acid-induced inflammation to kidney tubular cells through the ROS/NLRP3 pathway. Pharmacologic inhibition of LDHA or ROS in kidney tubular cells can significantly ameliorate inflammation response caused by uric acid. CONCLUSIONS: LDHA in kidney tubular cells significantly was increased in HUA models. LDHA mediates kidney inflammation response induced by uric acid through the ROS/NLRP3 pathway. This study may provide a new intervention target for preventing kidney tubular inflammation caused by uric acid.

Genetic and Physiological Effects of Insulin-Like Growth Factor-1 (IGF-1) on Human Urate Homeostasis.

SIGNIFICANCE STATEMENT: Hyperinsulinemia induces hyperuricemia by activating net renal urate reabsorption in the renal proximal tubule. The basolateral reabsorptive urate transporter GLUT9a appears to be the dominant target for insulin. By contrast, IGF-1 infusion reduces serum urate (SU), through mechanisms unknown. Genetic variants of IGF1R associated with reduced SU have increased IGF-1R expression and interact with genes encoding the GLUT9 and ABCG2 urate transporters, in a sex-specific fashion, which controls the SU level. Activation of IGF-1/IGF-1R signaling in Xenopus oocytes modestly activates GLUT9a and inhibits insulin's stimulatory effect on the transporter, which also activates multiple secretory urate transporters-ABCG2, ABCC4, OAT1, and OAT3. The results collectively suggest that IGF-1 reduces SU by activating secretory urate transporters and inhibiting insulin's action on GLUT9a. BACKGROUND: Metabolic syndrome and hyperinsulinemia are associated with hyperuricemia. Insulin infusion in healthy volunteers elevates serum urate (SU) by activating net urate reabsorption in the renal proximal tubule, whereas IGF-1 infusion reduces SU by mechanisms unknown. Variation within the IGF1R gene also affects SU levels. METHODS: Colocalization analyses of a SU genome-wide association studies signal at IGF1R and expression quantitative trait loci signals in cis using COLOC2, RT-PCR, Western blotting, and urate transport assays in transfected HEK 293T cells and in Xenopus laevis oocytes. RESULTS: Genetic association at IGF1R with SU is stronger in women and is mediated by control of IGF1R expression. Inheritance of the urate-lowering homozygous genotype at the SLC2A9 locus is associated with a differential effect of IGF1R genotype between men and women. IGF-1, through IGF-1R, stimulated urate uptake in human renal proximal tubule epithelial cells and transfected HEK 293T cells, through activation of IRS1, PI3/Akt, MEK/ERK, and p38 MAPK; urate uptake was inhibited in the presence of uricosuric drugs, specific inhibitors of protein tyrosine kinase, PI3 kinase (PI3K), ERK, and p38 MAPK. In X. laevis oocytes expressing ten individual urate transporters, IGF-1 through endogenous IGF-1R stimulated urate transport mediated by GLUT9, OAT1, OAT3, ABCG2, and ABCC4 and inhibited insulin's stimulatory action on GLUT9a and OAT3. IGF-1 significantly activated Akt and ERK. Specific inhibitors of PI3K, ERK, and PKC significantly affected IGF-1 stimulation of urate transport in oocytes. CONCLUSIONS: The combined results of infusion, genetics, and transport experiments suggest that IGF-1 reduces SU by activating urate secretory transporters and inhibiting insulin's action.

Alterations in the gut microbiome and metabolism profiles reveal the possible molecular mechanism of renal injury induced by hyperuricemia in a mouse model of renal insufficiency.

Objectives: To investigate the role of the intestinal flora and metabolites in the development of hyperuricemic renal injury in chronic kidney disease (CKD).Methods: Unilaterally nephrectomized mice were fed with adenine and potassium oxonate for 9 weeks. HE staining combined with plasma biochemical indicators was used to evaluate renal pathological and functional changes. We conducted 16S rRNA sequencing and untargeted metabolomics on feces and plasma samples to reveale changes in intestinal microbiota and metabolites.Result: Our analysis revealed significant differences in 15 bacterial genera, with 7 being upregulated and 8 being downregulated. Furthermore, metabolomic analysis revealed changes in the distribution of amino acid and biotin metabolites in basic metabolic pathways in both feces and serum. Specifically, differentially abundant metabolites in feces were associated primarily with histidine metabolism; the biosynthesis of phenylalanine, tyrosine, and tryptophan; and tyrosine metabolism. In plasma, the differentially abundant metabolites were involved in multiple metabolic pathways, including aminoacyl-tRNA biosynthesis; glycine, serine, and threonine amino acid metabolism; valine, leucine, and isoleucine biosynthesis; tyrosine biosynthesis and metabolism; biotin metabolism; and taurine and hypotaurine metabolism. Furthermore, correlation analysis revealed that Akkermansia, UCG-005, Lachnospiraceae_NK4A136_group, Lactococcus, and Butymonas were associated with various differentially abundant metabolites as well as renal function, oxidative stress, and mitophagy. The changes in the intestinal flora observed in hyperuricemia may lead to imbalances in amino acid and biotin metabolism in both the intestine and host, ultimately affecting oxidative stress and mitophagy in mice and accelerating the progression of CKD.Conclusion: Our findings provide insights into a potential pathogenic mechanism by which hyperuricemia exacerbates renal injury in mice with renal insufficiency. Understanding these pathways may offer new therapeutic strategies for managing hyperuricemic renal injury in CKD patients.

Plantaginis Semen Ameliorates Hyperuricemia Induced by Potassium Oxonate.

Plantaginis semen is the dried ripe seed of Plantago asiatica L. or Plantago depressa Willd., which has a long history in alleviating hyperuricemia (HUA) and chronic kidney diseases. While the major chemical ingredients and mechanism remained to be illustrated. Therefore, this work aimed to elucidate the chemicals and working mechanisms of PS for HUA. UPLC-QE-Orbitrap-MS was applied to identify the main components of PS in vitro and in vivo. RNA sequencing (RNA-seq) was conducted to explore the gene expression profile, and the genes involved were further confirmed by real-time quantitative PCR (RT-qPCR). A total of 39 components were identified from PS, and 13 of them were detected in the rat serum after treating the rat with PS. The kidney tissue injury and serum uric acid (UA), xanthine oxidase (XOD), and cytokine levels were reversed by PS. Meanwhile, renal urate anion transporter 1 (Urat1) and glucose transporter 9 (Glut9) levels were reversed with PS treatment. RNA-seq analysis showed that the PPAR signaling pathway; glycine, serine, and threonine metabolism signaling pathway; and fatty acid metabolism signaling pathway were significantly modified by PS treatment. Further, the gene expression of Slc7a8, Pck1, Mgll, and Bhmt were significantly elevated, and Fkbp5 was downregulated, consistent with RNA-seq results. The PPAR signaling pathway involved Pparα, Pparγ, Lpl, Plin5, Atgl, and Hsl were elevated by PS treatment. URAT1 and PPARα proteins levels were confirmed by Western blotting. In conclusion, this study elucidates the chemical profile and working mechanisms of PS for prevention and therapy of HUA and provides a promising traditional Chinese medicine agency for HUA prophylaxis.

[Modern understanding of uric acid metabolism disorders and progress in traditional Chinese medicine prevention and treatment].

The abnormal production and/or excretion of uric acid can lead to a disorder in uric acid metabolism, resulting in hyperuricemia, uric acid nephropathy, gouty arthritis, and other diseases related to uric acid metabolism disorder. The clinical incidence of these diseases is increasing year after year, posing a significant threat to public health. In the past, hyperuricemia and gouty arthritis were often considered different diseases, with uric acid nephropathy being a complication of hyperuricemia. However, recent research has challenged this perspective, suggesting that hyperuricemia, uric acid nephropathy, and gouty arthritis are different stages of the same disease, with urate deposition as the common pathological feature. This article offered a comprehensive overview of the current understanding of hyperuricemia, uric acid nephropathy, and gouty arthritis in both traditional Chinese medicine(TCM) and western medicine. It delved into the most up-to-date insights into the involvement of urate deposition in the pathogenesis of uric acid metabolism disorders and highlighted the dominant role of TCM in the prevention and treatment of uric acid metabolism disorders, so as to provide a reference for effective intervention strategies and drug development in uric acid metabolism disorder-related diseases.

Peptide NCTX15 derived from spider toxin gland effectively relieves hyperuricemia in mice.

Hyperuricemia is a clinical disease characterized by a continuous increase in uric acid (UA) due to purine metabolism disorder. As current drug treatments are limited, it is imperative to explore new drugs that offer better safety and efficacy. In this study, Nephila clavata toxin gland homogenates were isolated and purified by exclusion chromatography and high-performance liquid chromatography, resulting in the identification and isolation of a short peptide (NCTX15) with the sequence 'QSGHTFK'. Analysis showed that NCTX15 exhibited no cytotoxicity in mouse macrophages or toxic and hemolytic activity in mice. Notably, NCTX15 inhibited UA production by down-regulating urate transporter 1 and glucose transporter 9 and up-regulating organic anion transporter 1, thus promoting UA excretion. In addition, NCTX15 alleviated the inflammatory response and renal injury by inhibiting the expression of inflammatory factors interleukin-6, interleukin-1ß, tumor necrosis factor alpha, NLR family, pyrin domain-containing 3, and pyroptosis-related factor gasdermin D. These results indicate that NCTX15 displayed urate-lowering, anti-inflammatory, and analgesic effects. As the first urate-reducing short peptide isolated from a spider toxin gland homogenate, NCTX15 exhibits considerable potential as a novel drug molecule for anti-gout and hyperuricemia treatment.

Mechanistic insights of soluble uric acid-induced insulin resistance: Insulin signaling and beyond.

Hyperuricemia is a metabolic disease caused by purine nucleotide metabolism disorder. The prevalence of hyperuricemia is increasing worldwide, with a growing trend in the younger populations. Although numerous studies have indicated that hyperuricemia may be an independent risk factor for insulin resistance, the causal relationship between the two is controversial. There are few reviews, however, focusing on the relationship between uric acid (UA) and insulin resistance from experimental studies. In this review, we summarized the experimental models related to soluble UA-induced insulin resistance in pancreas and peripheral tissues, including skeletal muscles, adipose tissue, liver, heart/cardiomyocytes, vascular endothelial cells and macrophages. In addition, we summarized the research advances about the key mechanism of UA-induced insulin resistance. Moreover, we attempt to identify novel targets for the treatment of hyperuricemia-related insulin resistance. Lastly, we hope that the present review will encourage further researches to solve the chicken-and-egg dilemma between UA and insulin resistance, and provide strategies for the pathogenesis and treatment of hyperuricemia related metabolic diseases.

Hypouricemic Actions of the Pericarp of Mangosteen in Vitro and in Vivo.

Hyperuricemia is the result of overproduction and/or underexcretion of uric acid, and it is a well-known risk factor for gout, hypertension, and diabetes. However, available drugs for hyperuricemia in the clinic are limited. Recently, a lot of research has been conducted in order to discover new uric acid-lowering agents from plants and foods. We found that the extracts from the pericarp of mangosteen reduced urate. Bioactivity-guided study showed that α-mangostin was the principal constituent. Herein, we reported for the first time the hypouricemic activities and underling mechanism of α-mangostin. The α-mangostin dose- and time-dependently decreased the levels of serum urate in hyperuricemic mice and markedly increased the clearance of urate in hyperuricemic rats, exhibiting a promotion of urate excretion in the kidney. Further evidence showed that α-mangostin significantly decreased the protein levels of GLUT9 in the kidneys. The change in the expression of URAT1 was not observed. Moreover, α-mangostin did not inhibit the activities of xanthine oxidoreductase and uricase in vitro or in vivo. Taken together, these findings suggest that α-mangostin has potential to be developed as a new anti-hyperuricemic agent with promoting uric acid excretion.

Discovery and Characterization of Moracin C as an Anti-Gouty Arthritis/Hyperuricemia Candidate by Docking-Based Virtual Screening and Pharmacological Evaluation.

In the present study, a natural product database of compounds associated with herbs traditionally verified to treat gout/hyperuricemia/arthritis was constructed. 3D-shape and docking-based virtual screening was conducted. To identify potential xanthine oxidase (XOD) inhibitors in the database, eight compounds with commercial availability were identified as high 3D-shape similarity with febuxostat (1), a known XOD inhibitor. Docking was used to further predict the possible interactions between XOD and these compounds. Moracin C (2), moracin D (3), and isoformononetin (8) exhibited higher docking scores and binding energies than other compounds. In vitro, 2 inhibited XOD with an IC50 value of 0.25 ± 0.14 µM, which is similar to that of 1 (0.16 ± 0.08 µM). In a hyperuricemic mouse model, 5-20 mg/kg 2 exhibited satisfying urate-lowering and XOD inhibitory effects. Compound 2 also exhibited antiarthritis activities. In RAW264.7 cells, 2 at 1-10 µM inhibited the expression of IL-1ß and TNF-α induced by MSU. In an acute gouty arthritis model in SD rats, 5-20 mg/kg 2 significantly alleviated the toe swelling, inflammatory response, and dysfunction disorder caused by monosodium urate (MSU). Compound 2 inhibited serum IL-1ß and TNF-α cytokines as well as reduced the expression of the NLRP3/ASC/caspase-1 inflammasome in joints. In summary, 2 was an effective compound for the treatment of hyperuricemia/gouty arthritis.