Is lactic acid a misunderstood trigger of gout attack for a century?

A gout attack could be viewed as a nucleation event. Many reports have shown that the typical molecular structure of crystallization inhibitors usually contains carboxyl and hydroxyl groups, which could interact with solute molecules through hydrogen bonding, thereby suppressing the nucleation and growth of crystals. Since 1923, l-lactic acid (LA), a molecule with structural features of inhibitors, has been speculated to be a trigger for acute gout because metabolized LA temporarily reduces uric acid excretion and leads to a slow increase in serum uric acid concentration. However, many cases of gout presumably triggered by elevated lactate in a very short period of 4 h are often inexplicable. Here, we present the unexpected result that LA has a significant "opposite effect" on the nucleation and growth of gouty pathological crystals, which is that as the concentration of the additive LA increases, the nucleation and growth of the crystals is suppressed and then facilitated. This approach may help our clarifying the long-standing "misunderstandings" and further understanding the association between metabolized LA and increased risk of gout attacks. Finally, a novel mechanism called "tailed-made occupancy (TMO)" was used to explain the nucleation and crystallization effects of LA on sodium urate monohydrate (MSUM).

Design, synthesis, and biological evaluation of 3-phenyl substituted pyridine derivatives as potential dual inhibitors of XOR and URAT1.

Xanthine oxidoreductase (XOR) and uric acid transporter 1 (URAT1) are two most widely studied targets involved in production and reabsorption of uric acid, respectively. Marketed drugs almost target XOR or URAT1, but sometimes, single agents might not achieve aim of lowering uric acid to ideal value in clinic. Thus, therapeutic strategies of combining XOR inhibitors with uricosuric drugs were proposed and implemented. Based on our initial work of virtual screening, A and B were potential hits for dual-targeted inhibitors on XOR/URAT1. By docking A/B with XOR/URAT1 respectively, compounds I1-7 were designed to get different degree of inhibition effect on XOR and URAT1, and I7 showed the best inhibitory effect on XOR (IC50 = 0.037 ± 0.001 µM) and URAT1 (IC50 = 546.70 ± 32.60 µM). Further docking research on I7 with XOR/URAT1 led to the design of compounds II with the significantly improved inhibitory activity on XOR and URAT1, such as II11 and II15. Especially, for II15, the IC50 of XOR is 0.006 ± 0.000 µM, superior to that of febuxostat (IC50 = 0.008 ± 0.000 µM), IC50 of URAT1 is 12.90 ± 2.30 µM, superior to that of benzbromarone (IC50 = 27.04 ± 2.55 µM). In acute hyperuricemia mouse model, II15 showed significant uric acid lowering effect. The results suggest that II15 had good inhibitory effect on XOR/URAT1, with the possibility for further investigation in in-vivo models of hyperuricemia.

Spilanthes filicaulis (Schumach. & Thonn.) C.D. Adams leaves protects against streptozotocin-induced diabetic nephropathy.

BACKGROUND AND OBJECTIVE: Diabetic neuropathy (DN) is a complex type of diabetes. The underlying cause of diabetic nephropathy remains unclear and may be due to a variety of pathological conditions resulting in kidney failure. This study examines the protective effect of the methanolic extract of Spilanthes filicaulis leaves (MESFL) in fructose-fed streptozotocin (STZ)-induced diabetic nephropathy and the associated pathway. METHODS: Twenty-five rats were equally divided randomly into five categories: Control (C), diabetic control, diabetic + metformin (100 mg/kg), diabetic + MESFL 150 mg/kg bw, and diabetic + MESFL 300 mg/kg bw. After 15 days, the rats were evaluated for fasting blood glucose (FBG), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), urea, uric acid, serum creatinine, reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and lipid peroxidation (MDA). Gene expression levels of cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), cAMP response element-binding (CREB), cFOS and the antiapoptotic protein Bcl-2 were examined. RESULTS: We observed that MESFL at 150 and 300 mg/kg bw significantly downregulated the protein expression of cAMP, PKA, CREB, and cFOS and upregulated the Bcl-2 gene, suggesting that the nephroprotective action of MESFL is due to the suppression of the cAMP/PKA/CREB/cFOS signaling pathway. In addition, MESFL increases SOD and CAT activities and GSH levels, reduces MDA levels, and reduces renal functional indices (ALP, urea, uric acid, and creatinine). CONCLUSION: Therefore, our results indicate that MESFL alleviates the development of diabetic nephropathy via suppression of the cAMP/PKA/CREB/cFOS pathways.

Pathogenesis of gout: Exploring more therapeutic target.

Gout is a chronic metabolic and immune disease, and its specific pathogenesis is still unclear. When the serum uric acid exceeds its saturation in the blood or tissue fluid, it is converted to monosodium urate crystals, which lead to acute arthritis of varying degrees, urinary stones, or irreversible peripheral joint damage, and in severe cases, impairment of vital organ function. Gout flare is a clinically significant state of acute inflammation in gout. The current treatment is mostly anti-inflammatory analgesics, which have numerous side effects with limited treatment methods. Gout pathogenesis involves many aspects. Therefore, exploring gout pathogenesis from multiple perspectives is conducive to identifying more therapeutic targets and providing safer and more effective alternative treatment options for patients with gout flare. Thus, this article is of great significance for further exploring the pathogenesis of gout. The author summarizes the pathogenesis of gout from four aspects: signaling pathways, inflammatory factors, intestinal flora, and programmed cell death, focusing on exploring more new therapeutic targets.

Gut microbiota plays a significant role in gout.

With the development of social economy, the incidence of gout is increasing, which is closely related to people's increasingly rich diet. Eating a diet high in purine, fat, sugar and low-fibre for a long time further aggravates gout by affecting uric acid metabolism. The renal metabolism mechanism of uric acid has been thoroughly studied. To find a new treatment method for gout, increasing studies have recently been conducted on the mechanism of intestinal excretion, metabolism and absorption of uric acid. The most important research is the relationship between intestinal microbiota and the risk of gout. Gut microbiota represent bacteria that reside in a host's gastrointestinal tract. The composition of the gut microbiota is associated with protection against pathogen colonization and disease occurrence. This review focuses on how gut microbiota affects gout through uric acid and discusses the types of bacteria that may be involved in the occurrence and progression of gout. We also describe potential therapy for gout by restoring gut microbiota homeostasis and reducing uric acid levels. We hold the perspective that changing intestinal microbiota may become a vital method for effectively preventing or treating gout.

Signaling pathways in uric acid homeostasis and gout: From pathogenesis to therapeutic interventions.

Uric acid is a product of purine degradation, and uric acid may have multiple physiologic roles, including the beneficial effects as an antioxidant and neuroprotector, maintenance of blood pressure during low salt ingestion, and modulation of immunity. However, overproduction of metabolic uric acid, and/or imbalance of renal uric acid secretion and reabsorption, and/or underexcretion of extrarenal uric acid, e.g. gut, will contribute to hyperuricemia, which is a common metabolic disease. Long-lasting hyperuricemia can induce the formation and deposition of monosodium urate (MSU) crystals within the joints and periarticular structures. MSU crystals further induce an acute, intensely painful, and sterile inflammation conditions named as gout by NLRP3 inflammasome-mediated cleavage of pro-IL-1ß to bioactive IL-1ß. Moreover, hyperuricemia and gout are associated with multiple cardiovascular and renal disorders, e.g., hypertension, myocardial infarction, stroke, obesity, hyperlipidemia, type 2 diabetes mellitus and chronic kidney disease. Although great efforts have been made by scientists of modern medicine, however, modern therapeutic strategies with a single target are difficult to exert long-term positive effects, and even some of these agents have severe adverse effects. The Chinese have used the ancient classic prescriptions of traditional Chinese medicine (TCM) to treat metabolic diseases, including gout, by multiple targets, for more than 2200 years. In this review, we discuss the current understanding of urate homeostasis, the pathogenesis of hyperuricemia and gout, and both modern medicine and TCM strategies for this commonly metabolic disorder. We hope these will provide the good references for treating hyperuricemia and gout.

Potential Anti-Gouty Arthritis of Citronella Essential Oil and Nutmeg Essential Oil through Reducing Oxidative Stress and Inhibiting PI3K/Akt/mTOR Activation-Induced NLRP3 Activity.

Citronella and Nutmeg are two common spices used for seasoning and medicinal purposes, both of which have significant economic value. This study aimed to investigate whether Citronella essential oil and Nutmeg essential oil (NEO) can ameliorate monosodium urate (MSU)-induced gouty arthritis in rats and the potential mechanisms. The results showed that CEO and NEO reduced swelling and redness at joint sites, inhibited neutrophil infiltration, and limited proinflammatory mediator secretion in mice with MSU-induced gouty arthritis. Based on the results of network pharmacology, molecular docking, and western blotting, CEO and NEO may exert anti-gouty arthritis effects by reducing the expression of reactive oxygen species and oxidative stress and downregulating the phosphorylation of the PI3K/AKT/mTOR signaling pathway, thereby inhibiting the production of the NLRP3 inflammasome and inhibiting the production of inflammatory cytokines. Therefore, these two essential oils show potential for use as adjuvant treatments for gouty arthritis in specific aromatherapy products or food seasonings.

Exploring the anti-gout potential of sunflower receptacles alkaloids: A computational and pharmacological analysis.

Gout, a painful condition marked by elevated uric acid levels often linked to the diet's high purine and alcohol content, finds a potential treatment target in xanthine oxidase (XO), a crucial enzyme for uric acid production. This study explores the therapeutic properties of alkaloids extracted from sunflower (Helianthus annuus L.) receptacles against gout. By leveraging computational chemistry and introducing a novel R-based clustering algorithm, "TriDimensional Hierarchical Fingerprint Clustering with Tanimoto Representative Selection (3DHFC-TRS)," we assessed 231 alkaloid molecules from sunflower receptacles. Our clustering analysis pinpointed six alkaloids with significant gout-targeting potential, particularly emphasizing the fifth cluster's XO inhibition capabilities. Through molecular docking and the BatchDTA prediction model, we identified three top compounds-2-naphthylalanine, medroxalol, and fenspiride-with the highest XO affinity. Further molecular dynamics simulations assessed their enzyme active site interactions and binding free energies, employing MM-PBSA calculations. This investigation not only highlights the discovery of promising compounds within sunflower receptacle alkaloids via LC-MS but also introduces medroxalol as a novel gout treatment candidate, showcasing the synergy of computational techniques and LC-MS in drug discovery.

Investigation of the protective effect of chitosan against arsenic-induced nephrotoxicity and oxidative damage in rat kidney tissue.

Arsenic is an important metalloid that can cause poisoning in humans and domestic animals. Exposure to arsenic causes cell damage, increasing the production of reactive oxygen species. Chitosan is a biopolymer obtained by deacetylation of chitin with antioxidant and metal ion chelating properties. In this study, the protective effect of chitosan on arsenic-induced nephrotoxicity and oxidative damage was investigated. 32 male Wistar-albino rats were divided into 4 groups of 8 rats each as control group (C), chitosan group (CS group), arsenic group (AS group), and arsenic+chitosan group (AS+CS group). The C group was given distilled water by oral gavage, the AS group was given 100 ppm/day Na-arsenite ad libitum with drinking water, the CS group was given 200 mg/kg/day chitosan dissolved in saline by oral gavage, the AS+CS group was given 100 ppm/day Na-arsenite ad libitum with drinking water and 200 mg/kg/day chitosan dissolved in saline by oral gavage for 30 days. At the end of the 30-day experimental period, 90 mg/kg ketamine was administered intraperitoneally to all rats, and blood samples and kidney tissues were collected. Urea, uric acid, creatinine, P, Mg, K, Ca, Na, Cystatin C (CYS-C), Neutrophil Gelatinase Associated Lipocalin (NGAL) and Kidney Injury Molecule 1 (KIM-1) levels were measured in serum samples. Malondialdehyde (MDA), Glutathione (GSH), Catalase (CAT) and Superoxide dismutase (SOD) levels in the supernatant obtained from kidney tissue were analyzed by ELISA method. Compared with AS group, uric acid and creatinine levels of the AS+CS group were significantly decreased (p<0.001), urea, KIM-1, CYS-C, NGAL, and MDA levels were numerically decreased and CAT, GSH, and SOD levels were numerically increased (p>0.05). In conclusion, based on both biochemical and histopathological-immunohistochemical- immunofluorescence findings, it can be concluded that chitosan attenuates kidney injury and protects the kidney.

Piperine Improves Hyperuricemic Nephropathy by Inhibiting URAT1/GLUT9 and the AKT-mTOR Pathway.

Uncontrolled hyperuricemia often leads to the development of hyperuricemic nephropathy (HN), characterized by excessive inflammation and oxidative stress. Piperine, a cinnamic acid alkaloid, possesses various pharmacological activities, such as antioxidant and anti-inflammatory effects. In this study, we intended to investigate the protective effects of piperine on adenine and potassium oxonate-induced HN mice and a uric-acid-induced injury model in renal tubular epithelial cells (mRTECs). We observed that treatment with piperine for 3 weeks significantly reduced serum uric acid levels and reversed kidney function impairment in mice with HN. Piperine (5 µM) alleviated uric acid-induced damage in mRTECs. Moreover, piperine inhibited transporter expression and dose-dependently inhibited the activity of both transporters. The results revealed that piperine regulated the AKT/mTOR signaling pathway both in vivo and in vitro. Overall, piperine inhibits URAT1/GLUT9 and ameliorates HN by inhibiting the AKT/mTOR pathway, making it a promising candidate for patients with HN.

Interaction-based screening, Monte Carlo Bayesian inference-based de novo design and in vitro verification of adenine-binding peptide.

One of the main reasons for hyperuricemia is high purine intake. The primary strategy for treating hyperuricemia is blocking the purine metabolism enzyme. However, by binding the purine bases directly, we suggested a unique therapeutic strategy that might interfere with purine metabolism. There have been numerous reports of extensive interactions between proteins and purine bases. Adenine, constituting numerous protein co-factors, can interact with the adenine-binding motif. Using Bayesian Inference and Markov chain Monte Carlo sampling, we created a novel adenine-binding peptide Ile-Tyr-Val-Thr based on the structure of the adenine-binding motifs. Ile-Tyr-Val-Thr generates a semi-pocket that can clip the adenine within, as demonstrated by docking. Then, using thermodynamic techniques, the interaction between Ile-Tyr-Val-Thr and adenine was confirmed. The KD value is 1.50e-5 (ΔH = -20.2 kJ/mol and ΔG = -27.6 kJ/mol), indicating the high affinity. In brief, the adenine-binding peptide Ile-Tyr-Val-Thr may help lower uric acid level by blocking the absorption of food-derived adenine.

A Possible Therapeutic Application of the Selective Inhibitor of Urate Transporter 1, Dotinurad, for Metabolic Syndrome, Chronic Kidney Disease, and Cardiovascular Disease.

The reabsorption of uric acid (UA) is mainly mediated by urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) in the kidneys. Dotinurad inhibits URAT1 but does not inhibit other UA transporters, such as GLUT9, ATP-binding cassette transporter G2 (ABCG2), and organic anion transporter 1/3 (OAT1/3). We found that dotinurad ameliorated the metabolic parameters and renal function in hyperuricemic patients. We consider the significance of the highly selective inhibition of URAT1 by dotinurad for metabolic syndrome, chronic kidney disease (CKD), and cardiovascular disease (CVD). The selective inhibition of URAT1 by dotinurad increases urinary UA in the proximal tubules, and this un-reabsorbed UA may compete with urinary glucose for GLUT9, reducing glucose reabsorption. The inhibition by dotinurad of UA entry via URAT1 into the liver and adipose tissues increased energy expenditure and decreased lipid synthesis and inflammation in rats. Such effects may improve metabolic parameters. CKD patients accumulate uremic toxins, including indoxyl sulfate (IS), in the body. ABCG2 regulates the renal and intestinal excretion of IS, which strongly affects CKD. OAT1/3 inhibitors suppress IS uptake into the kidneys, thereby increasing plasma IS, which produces oxidative stress and induces vascular endothelial dysfunction in CKD patients. The highly selective inhibition of URAT1 by dotinurad may be beneficial for metabolic syndrome, CKD, and CVD.

Tetrandrine alleviates inflammation and promotes macrophage M2 polarization in gouty arthritis by NF-κB-mediated Lcp1.

Gouty arthritis (GA) is an inflammatory disease caused by the deposition of monosodium urate (MSU) crystals into joints. Tetrandrine (TET) is a bisbenzylisoquinoline alkaloid extracted from the root of Stephania tetrandra and can exert an anti-inflammatory function in different diseases. Nevertheless, the specific function of TET in GA remains unclear. We established the GA mouse model by MSU injection into joints of mice. Paw volume and gait score were detected for measuring the degree of joint swelling and the situation of joint dysfunction. Western blot were utilized to test the alterations of M1-related factors (IL-6, IL-1ß, TNF-α, IL-12, and iNOS) and M2-related factors (Mgl1, Mgl2, Pgc1-ß, Arg-1, and IL-10). The activity of NF-κB p65 in tissues was determined. The interaction of NF-κB p65 and Lcp1 was measured by ChIP and luciferase reporter assay. Lcp1 KO mice were utilized to detect the effect of Lcp1 depletion on GA process. TET treatment markedly suppressed MSU-induced joint swelling, joint dysfunction, and joint injury in GA mice. TET can also reduce inflammatory reactions in MUS-induced mice. Furthermore, we proved that TET facilitated M2 macrophage polarization and inhibited M1 macrophage polarization in GA mice. In addition, TET was found to inhibit NF-κB activity and NF-κB-mediated Lcp1 expression. Lcp1 knockdown can improve joint injury and promote M2 macrophage polarization in GA mice, while this effect was further enhanced by TET. TET alleviates inflammation and facilitates macrophage M2 polarization in GA by NF-κB-mediated Lcp1.

Proline-derived quinoline formamide compounds as human urate transporter 1 inhibitors with potent uric acid-lowering activities.

We report the design and synthesis of a series of proline-derived quinoline formamide compounds as human urate transporter 1 (URAT1) inhibitors via a ligand-based pharmacophore approach. Structure-activity relationship studies reveal that the replacement of the carboxyl group on the polar fragment with trifluoromethanesulfonamide and substituent modification at the 6-position of the quinoline ring greatly improve URAT1 inhibitory activity compared with lesinurad. Compounds 21c, 21e, 24b, 24c, and 23a exhibit potent activities against URAT1 with IC50 values ranging from 0.052 to 0.56 µM. Furthermore, compound 23a displays improved selectivity towards organic anion transporter 1 (OAT1), good microsomal stability, low potential for genotoxicity and no inhibition of the hERG K+ channel. Compounds 21c and 23a, which have superior pharmacokinetic properties, also demonstrate significant uric acid-lowering activities in a mouse model of hyperuricemia. Notably, 21c also exhibits moderate anti-inflammatory activity related to the gout inflammatory pathway. Compounds 21c and 23a with superior druggability are potential candidates for the treatment of hyperuricemia and gout.

Pesticides compromise health: a comparison between lizards collected within and outside an agricultural area.

Reptiles are the least studied vertebrates regarding the impact of pesticides on their health, despite being good models for ecotoxicological studies given their abundance and easy handling. Salvator merianae is widely distributed in South America and often found in agricultural cultivation areas. Here, we compared the morphological, biochemical, and physiological parameters of S. merianae from an exposed area (EA) to pesticides and a reference area (RA) or control. These parameters were measured in plasma (albumin, alanine transaminase, alkaline phosphatase, gamma-glutamyl transpeptidase, glucose, total proteins, uric acid, triglycerides, VLDL, and corticosterone) and in erythrocytes (TBARS, glutathione S-transferase, superoxide dismutase, and catalase activity). Blood samples were collected from 28 lizards (EA: three juveniles, three adult females, and three adult males; RA: nine juveniles, four females, and five males) in southern Brazil during the reproductive period. We observed a decrease in body mass, the ratio between body mass and total length and snout-vent length in juvenile lizards collected at EA. The levels of TBARS, glutathione S-transferase, triglycerides, VLDL, and uric acid were altered for juveniles in EA. When comparing the two areas, females differed in superoxide dismutase activity and total proteins, while males differed in superoxide dismutase, catalase, and glutathione S-transferase activity. This set of results shows that S. merianae, especially juveniles, suffers a negative impact when inserted in an agricultural area. The analyzed biomarkers proved suitable for monitoring these lizards and the quality of this environment.

Bidirectional effect of uric acid on C2C12 myotubes and its partial mechanism.

AIM: To explore the effects and mechanisms of different concentrations of uric acid on skeletal muscle cells. METHODS: C2C12 myoblasts were differentiated into myotubes and then exposed to a medium containing uric acid (0 µM, 200 µM, 400 µM, 600 µM, 800 µM, 1000 µM, 1200 µM, 1400 µM). The myotube diameters were observed under light microscopy; the expressions of myosin heavy chain (MyHC), autophagy-related proteins (LC3BII/LC3BI, P62), cGAS, and p-Sting/Sting proteins were analyzed using Western blotting or immunoprecipitation; and oxidative stress and mitochondrial damage were evaluated using ROS, mtDNA and JC-1 assays. Cell viability was measured via CCK8 assay, and 1000-µM uric acid was selected for follow-up experiments. Furthermore, C2C12 myotubes were divided into a blank control group (Ctrl), a high-uric-acid group (HUA), and an HUA plus cGASn inhibitor group (HUA + RU.521). Then, the myotube diameter was observed, oxidative stress and mitochondrial damage were evaluated, and MyHC and autophagy-related protein expressions were analysed. RESULTS: C2C12 myotubes cultured in 400-µM uric acid medium had the greatest myotube diameter and the highest MyHC protein expression. At 1000-µM uric acid, the diameter and MyHC protein expression were significantly decreased, LCB3II/LCB3I expression was notably increased, and the level of p62 protein expression was considerably decreased. RU.521 partially alleviated the HUA-induced C2C12 myotubes changes. CONCLUSIONS: Uric acid bidirectionally affected C2C12 myotubes: 400-µΜ uric acid promoted myotube growth, while 1000-µΜ uric acid triggered myotube atrophy with increased autophagy. Inhibiting cGAS-Sting signaling attenuated HUA-induced C2C12 myotube autophagy and atrophy. Geriatr Gerontol Int 2024; 24: 430-439.

Crystal structure of the complex of CLEC12A and an antibody that interferes with binding of diverse ligands.

C-type lectin receptors (CLRs) are a family of pattern recognition receptors, which detect a broad spectrum of ligands via small carbohydrate-recognition domains (CRDs). CLEC12A is an inhibitory CLR that recognizes crystalline structures such as monosodium urate crystals. CLEC12A also recognizes mycolic acid, a major component of mycobacterial cell walls, and suppresses host immune responses. Although CLEC12A could be a therapeutic target for mycobacterial infection, structural information on CLEC12A was not available. We report here the crystal structures of human CLEC12A (hCLEC12A) in ligand-free form and in complex with 50C1, its inhibitory antibody. 50C1 recognizes human-specific residues on the top face of hCLEC12A CRD. A comprehensive alanine scan demonstrated that the ligand-binding sites of mycolic acid and monosodium urate crystals may overlap with each other, suggesting that CLEC12A utilizes a common interface to recognize different types of ligands. Our results provide atomic insights into the blocking and ligand-recognition mechanisms of CLEC12A and leads to the design of CLR-specific inhibitors.

Polyvinylpyrrolidone-Coated Cubic Hollow Nanocages of PdPt3 and PdIr3 as Highly Efficient Self-Cascade Uricase/Peroxidase Mimics.

Uricase-catalyzed uric acid (UA) degradation has been applied for hyperuricemia therapy, but this medication is limited by H2O2 accumulation, which can cause oxidative stress of cells, resulting in many other health issues. Herein, we report a robust cubic hollow nanocage (HNC) system based on polyvinylpyrrolidone-coated PdPt3 and PdIr3 to serve as highly efficient self-cascade uricase/peroxidase mimics to achieve the desired dual catalysis for both UA degradation and H2O2 elimination. These HNCs have hollow cubic shape with average wall thickness of 1.5 nm, providing desired synergy to enhance catalyst's activity and stability. Density functional theory calculations suggest the PdIr3 HNC surface tend to promote OH*/O* desorption for better peroxidase-like catalysis, while the PdPt3 HNC surface accelerates the UA oxidation by facilitating O2-to-H2O2 conversion. The dual catalysis power demonstrated by these HNCs in cell studies suggests their great potential as a new type of nanozyme for treating hyperuricemia.

Alistipes indistinctus-derived hippuric acid promotes intestinal urate excretion to alleviate hyperuricemia.

Hyperuricemia induces inflammatory arthritis and accelerates the progression of renal and cardiovascular diseases. Gut microbiota has been linked to the development of hyperuricemia through unclear mechanisms. Here, we show that the abundance and centrality of Alistipes indistinctus are depleted in subjects with hyperuricemia. Integrative metagenomic and metabolomic analysis identified hippuric acid as the key microbial effector that mediates the uric-acid-lowering effect of A. indistinctus. Mechanistically, A. indistinctus-derived hippuric acid enhances the binding of peroxisome-proliferator-activated receptor γ (PPARγ) to the promoter of ATP-binding cassette subfamily G member 2 (ABCG2), which in turn boosts intestinal urate excretion. To facilitate this enhanced excretion, hippuric acid also promotes ABCG2 localization to the brush border membranes in a PDZ-domain-containing 1 (PDZK1)-dependent manner. These findings indicate that A. indistinctus and hippuric acid promote intestinal urate excretion and offer insights into microbiota-host crosstalk in the maintenance of uric acid homeostasis.

Catalpol ameliorates fructose-induced renal inflammation by inhibiting TLR4/MyD88 signaling and uric acid reabsorption.

Accumulating evidence suggests that excess fructose uptake induces metabolic syndrome and kidney injury. Here, we primarily investigated the influence of catalpol on fructose-induced renal inflammation in mice and explored its potential mechanism. Treatment with catalpol improved insulin sensitivity and hyperuricemia in fructose-fed mice. Hyperuricemia induced by high-fructose diet was associated with increases in the expressions of urate reabsorptive transporter URAT1 and GLUT9. Treatment with catalpol decreased the expressions of URAT1 and GLUT9. Futhermore, treatment with catalpol ameliorated renal inflammatory cell infiltration and podocyte injury, and these beneficial effects were associated with inhibiting the production of inflammatory cytokines including IL-1ß, IL-18, IL-6 and TNF-α. Moreover, fructose-induced uric acid triggers an inflammatory response by activiting NLRP3 inflammasome, which then processes pro-inflammatory cytokines. Treatment with catalpol could inhibit the activation of NLRP3 inflammasome as well. Additionally, TLR4/MyD88 signaling was activated in fructose-fed mice, while treatment with catalpol inhibited this activation along with promoting NF-κB nuclear translocation in fructose-fed mice. Thus, our study demonstrated that catalpol could ameliorate renal inflammation in fructose-fed mice, attributing its beneficial effects to promoting uric acid excretion and inhibit the activation of TLR4/MyD88 signaling.