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Xanthine oxidase (XO) is an important enzyme that catalyzes the oxidation of hypoxanthine to xanthine and xanthine to uric acid in the catabolism of purines in humans. This makes XO a well-recognized target in alleviating hyperuricemia. The present study adapted a structure-based drug discovery approach to develop potent and low-toxicity XO inhibitors with the chalcone skeleton. We introduced a carboxyl group and a hydroxyl group to the B ring and modified the A ring. 35 chalcone derivatives were designed and synthesized. All the 35 derivatives exhibited higher XO inhibition activities (IC 50  = 0.064-0.559 μM) compared with allopurinol (IC 50  = 2.588 μM). Their high affinity was attributed to strong hydrogen bond interactions formed between the introduced carboxyl and hydroxyl groups with key amino acid residues in XO. SAR analysis disclosed that carboxyl, hydroxyl, ethyl (12c), methylamino (12h), dimethylamino (12i), indolin (13k), and indol (13l) groups played important roles in improving the whole molecules' inhibition potency against XO. ADME predictions and cytotoxicity assays suggested their pharmacokinetic characteristics and biocompatibility were desirable. Additionally, 12c exhibited a significant hypouricemic effect on potassium oxonate-induced hyperuricemia rats after orally administrated at a dose range of 10-40 mg/kg, representing a promising anti-hyperuricemia potential for further optimization and development., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Attempts to furnish antitumor structural templates that can prevent the occurrence of drug-induced hyperuricemia spurred us to generate xanthine oxidase inhibitor-based hydroxamic acids and anilides. Specifically, the design strategy involved the insertion of febuxostat (xanthine oxidase inhibitor) as a surface recognition part of the HDAC inhibitor pharmacophore model. Investigation outcomes revealed that hydroxamic acid 4 elicited remarkable antileukemic effects mediated via HDAC isoform inhibition. Delightfully, the adduct retained xanthine oxidase inhibitory activity, though xanthine oxidase inhibition was not the underlying mechanism of its cell growth inhibitory effects. Also, compound 4 demonstrated significant in-vivo anti-hyperuricemic (PO-induced hyperuricemia model) and antitumor activity in an HL-60 xenograft mice model. Compound 4 was conjugated with poly (ethylene glycol) poly(aspartic acid) block copolymer to furnish pH-responsive nanoparticles (NPs) in pursuit of circumventing its cytotoxicity towards the normal cell lines. SEM analysis revealed that NPs had uniform size distributions, while TEM analysis ascertained the spherical shape of NPs, indicating their ability to undergo self-assembly. HDAC inhibitor 4 was liberated from the matrix due to the polymeric nanoformulation's pH-responsiveness, and the NPs demonstrated selective cancer cell targeting ability., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

This study aimed to evaluate the preventive effect of Bi Xie Fen Qing Yin (BXFQY) decoction on hyperuricemic nephropathy (HN). Using an HN mouse model induced by oral gavage of potassium oxonate and adenine, we found that BXFQY significantly reduced plasma uric acid levels and improved renal function. Further study shows that BXFQY suppressed the activation of the NLRP3 inflammasome and decreased the mRNA expressions of pro-inflammatory and fibrosis-associated factors in renal tissues of HN mice. Also, BXFQY prevented the damage to intestinal tissues of HN mice, indicative of suppressed colonic inflammation and increased gut barrier integrity. By 16 S rDNA sequencing, BXFQY significantly improved gut microbiota dysbiosis of HN mice. On the one hand, BXFQY down-regulated the abundance of some harmful bacteria, like Desulfovibrionaceae, Enterobacter, Helicobacter, and Desulfovibrio. On the other hand, BXFQY up-regulated the contents of several beneficial microbes, such as Ruminococcaceae, Clostridium sensu stricto 1, and Streptococcus. Using gas or liquid chromatography-mass spectrometry (GC/LC-MS) analysis, BXFQY reversed the changes in intestinal bacterial metabolites of HN mice, including indole and BAs. The depletion of intestinal flora from HN or HN plus BXFQY mice confirmed the significance of gut microbiota in BXFQY-initiated treatment of HN. In conclusion, BXFQY can alleviate renal inflammation and fibrosis of HN mice by modulating gut microbiota and intestinal metabolites. This study provides new insight into the underlying mechanism of BXFQY against HN., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

In combination with allopurinol, tranilast is used as an urate transporter 1 (URAT1) inhibitor for the treatment of hyperuricemia, but its structure-activity relationship concerning URAT1 inhibitory activity is rarely studied. In this paper, analogs 1-30 were designed and synthesized using scaffold hopping strategy on the basis of tranilast and the privileged scaffold indole. Then, URAT1 activity was evaluated using 14 C-uric acid uptake assay with HEK293-URAT1 overexpressing cells. Compared with tranilast (inhibitory rate = 44.9% at 10 μM), most compounds displayed apparent inhibitory effects, ranging from 40.0% to 81.0% at 10 μM on URAT1. Surprisingly, along with the bringing in of a cyano group at the 5-position of indole ring, compounds 26 and 28-30 exerted xanthine oxidase (XO) inhibitory activity. In particular, compound 29 presented potency on URAT1 (48.0% at 10 μM) and XO (IC 50  = 1.01 μM). Molecular simulation analysis revealed that the basic structure of compound 29 had an affinity with URAT1, and XO. Furthermore, compound 29 demonstrated a significant hypouricemic effect in a potassium oxonate-induced hyperuricemia rat model at an oral dose of 10 mg/kg during in vivo tests. In summary, tranilast analog 29 was identified as a potent dual-target inhibitor of URAT1 and XO, and a promising lead compound for further investigation., Competing Interests: Declaration of competing interest We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Xanthine oxidase (XO) has emerged as an important target for the treatment of hyperuricemia and gout. In this study, to obtain novel nonpurine XO inhibitors, a series of 1-alkyl-5/6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1H-indole-3-carbonitriles (1a-1u, 2c, 2e, 2h and 2n) were designed using a bioisosteric replacement strategy and were synthesized through a five-step procedure with good yields. Thereafter, the in vitro XO inhibitory potencies of these compounds were evaluated by spectrophotometry, showing inhibitory profiles in the micromolar/submicromolar range. Particularly, compound 1h emerged as the strongest XO inhibitor, with an IC 50 value of 0.36 μM, which was approximately 21-fold more potent than the positive control allopurinol. Additionally, the structure-activity relationships revealed that the 5-oxo-4,5-dihydro-1,2,4-oxadiazole moiety linked at the 5-position of the indole scaffold was more preferable than the 6-position for the XO inhibitory potency. Enzyme kinetic studies indicated that compound 1h acted as a mixed-type XO inhibitor. Moreover, molecular modeling studies were performed on compound 1h to gain insights into its binding modes with XO. The results showed that the 5-oxo-4,5-dihydro-1,2,4-oxadiazole moiety could interact with Arg880 and Thr1010 in the innermost part of the active pocket through hydrogen bonds, while the cyano group could form hydrogen bonds with Asn768 and Lys771 in the subpocket. Furthermore, the in vivo hypouricemic effect of compound 1h was further investigated in a hyperuricemia rat model induced by potassium oxonate. The results suggested that compound 1h could effectively reduce serum uric acid levels at an oral dose of 10 mg/kg. Therefore, compound 1h could be a promising lead compound for the treatment of hyperuricemia and gout., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

As part of a continuing study, we designed and synthesized four series of 1-phenylimidazole-4-carboxylic acid derivatives as xanthine oxidoreductase (XOR) inhibitors, evaluated their in vitro inhibitory potencies against XOR and hypouricemic effects in mice, and determined their structure-activity relationships (SARs). Most of the compounds exhibited in vitro XOR inhibition at the nanomolar level. In comparison to febuxostat (half-maximal inhibitory concentration [IC 50 ] value of 7.0 nM), compounds Ie and IVa exhibited the most promising XOR inhibitory effects with IC 50 values of 8.0 and 7.2 nM, respectively. In the potassium oxonate/hypoxanthine-induced acute and long-term hyperuricemia mouse models, compounds Ie and IVa displayed significant hypouricemic potencies (P < 0.05), that were slightly weaker than and similar to febuxostat, respectively. More interestingly, both compounds showed a capacity to improve kidney damage by decreasing creatinine and urea nitrogen levels compared to the long-term hyperuricemia mouse group (P < 0.05), while febuxostat showed no significant effect., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Current evidences suggest that hyperuricemia is closely related to the overproduction or underexcretion of uric acid (UA). Curcumin (CUR), a natural polyphenol component extracted from the rhizome of Curcuma longa, has been reported to treat various symptoms such inflammation disease, seems to be efficacious in hyperuricemia. In this study, we aimed to investigate the effect of CUR on hyperuricemia and kidney inflammation in hyperuricemic mice. Administration with CUR (20 or 40 mg/kg) or allopurinol (ALL, 5 mg/kg) was given to mice orally one hour later after the injection of potassium oxonate (PO) (300 mg/kg, i.p.) for 14 days. CUR administration decreased the levels of uric acid (UA), creatinine (CRE) and blood urea nitrogen (BUN) in serum. Meanwhile, treatment with CUR effectively inhibited serum and liver xanthine oxidase (XOD) levels, and further renewed normal antioxidant enzymes activities (SOD, GSH-Px), reduced MDA accumulation in serum. Further studies showed that CUR decreased inflammatory cytokines productions (IL-1β, IL-18) in serum, as well as inhibited PO-induced the activation of NLRP3 inflammasome signaling in the kidney. In conclusion, the study revealed that CUR exhibited anti-hyperuricemic and anti-inflammatory effects through suppressing NLRP3 inflammasome activation in kidney and provided the evidence for treating hyperuricemia and associated renal inflammation., (Copyright © 2019 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Recent preclinical and clinical evidence suggests that hyperuricemia (HU) is an independent risk factor for metabolic syndrome, hypertension, cardiovascular disease and chronic kidney disease. Receptor-interacting protein 3 (RIP3) is an important contributor in inducing programmed necrosis, representing a newly identified mechanism of cell death combining features of both apoptosis and necrosis. In our study, RIP3 was strongly expressed in mice with hyperuricemia. RIP3 deficiency attenuated hyperuricemia in mice, evidenced by reduced serum uric acid and creatinine and enhanced urinary uric acid and creatinine, as well as the improved histological alterations in renal sections. Additionally, RIP3-deletion reduced malondialdehyde (MDA), H 2 O 2 and O 2 - , whereas enhanced superoxide dismutase (SOD), GSH and GSH-Px levels in potassium oxonate-induced mice. Potassium oxonate-treated mice showed significantly high mRNA levels of ATP-binding cassette, subfamily G, membrane 2 (ABCG2), organic anion transporter 1 (OAT1), OAT3, organic cation transporter 1 (OCT1) and organic cation/carnitine transporter 1 (OCTN1) in renal tissue samples, which were reversed by RIP3-deficiency. Meanwhile, down-regulation of circulating and kidney pro-inflammatory cytokines (IL-1β, TNF-α and IL-6) were observed in RIP3-knockout mice with hyperuricemia, associated with inactivation of toll-like receptor 4 (TLR4), inhibitor of NF-κB alpha (IκBα) and nuclear factor kappa B (NF-κB). NLR family, pyrin domain-containing 3 (NLRP3) inflammasome was also suppressed by RIP3 knockout in potassium oxonate-treated mice. Importantly, RIP3-knockout mice exhibited the decrease of FAS-associated protein with a death domain (FADD), cleaved Caspase-8/-3 and Poly (ADP-ribose) polymerase (PARP) in renal samples, along with TUNEL reduction in mice with hyperuricemia. Similar results were observed in uric acid-incubated cells with RIP3 knockdown. Thus, we suggested that RIP3 played an important role in mice with hyperuricemia, which might be a novel signal pathway targeting for therapeutic strategies in future., (Copyright © 2018. Published by Elsevier Masson SAS.)

Hyperuricemia is the term for an abnormally high serum uric acid level. Many factors contribute to hyperuricemia, however no definite correlation between proton pump inhibitors (PPIs) and hyperuricemia has been reported before. Physical exercise also decreases serum uric acid levels. However, the detailed biochemical-regulatory mechanisms remain unknown. Here we found that adenylate deaminase activities are much higher in hyperuricemia patients than in the healthy people. Therefore, the patients have higher levels of adenosine metabolites hypoxanthine and uric acid. Acid-inhibitory drugs (antacids) significantly increased serum uric acid level and may lead to gout in the hyperuricemia patient. Long-term aerobic exercise significantly increased serum phosphorus and decreased serum ATP and its metabolites, and therefore decreased serum uric acid. Antacids slow down the ATP turnover rate and result in serum uric acid elevation subsequently. While the long-term aerobic exercise decreases serum uric acid levels by accelerating ATP turnover rate. The results imply that long-term aerobic exercise may be a useful strategy to prevent and treat hyperuricaemia., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

A diverse library of 1-phenyl-pyrazole-4-carboxylic acid derivatives were synthesized and evaluated for their inhibitory potency against xanthine oxidoreductase (XOR) in vitro and vivo, and the structure-activity relationship (SAR) analyses were also presented. Approximately half of the target compounds exhibited the inhibitory potency for XOR at the nanomolar level. Compounds 16c, 16d, and 16f emerged as the most potent xanthine oxidoreductase inhibitors with IC 50 values of 5.7, 5.7 and 4.2 nM, respectively, in comparison to febuxostat (IC 50 of 5.4 nM). Steady-state kinetics measurements indicated that 16c is a mixed-type inhibitor. A computer molecular docking study of 16c bound to XOR was performed to gain an insight into its bind mode and SAR for the series. A potassium oxonate-hypoxanthine-induced hyperuricemia model in mice was chosen to further confirm the hypouricemic effects of 16c and 16f, and the results demonstrated that 16c exhibits similar hypouricemic potency to febuxostat., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

The aim is to investigate the anti-hyperuricemic and renal protective effects of liquiritigenin in potassium oxonate-induced hyperuricemic rats. Hyperuricemia in rats was induced were induced with potassium oxonate (250mg/kg) intragastrically for 7 days, and liquiritigenin (20, 40mg/kg) and allopurinol (5mg/kg) were daily administrated to the rats orally 1h after the potassium oxonate exposure. Liquiritigenin significantly reversed the elevated productions of uric acid in serum and urine and pro-inflammation cytokines in serum and kidney, which shown that liquiritigenin has renal protective effects. Histological study shows that liquiritigenin inhibited severe necrosis and inflammatory cell infiltration in potassium oxonate-treated rats. Furthermore, liquiritigenin mediated the activities of aquaporins 4 (AQP4), and regulated the activation of NF-κB p65 and the degradation of IκBα. Finally, significant increases of nod-like receptor protein 3 (NLRP3) inflammasome, apoptosis-associated speck-like protein adaptor (ASC) adaptor and cleaved caspased-1 were restored by liquiritigenin. Therefore, liquiritigenin might improve renal inflammation by suppressing renal AQP4/NF-κB/IκBα and NLRP3 inflammasome activation in hyperuricemic rats., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Astilbin is a flavonoid compound derived from the rhizome of Smilax china L. The effects and possible molecular mechanisms of astilbin on potassium oxonate-induced hyperuricemia mice were investigated in this study. Different dosages of astilbin (5, 10, and 20mg/kg) were administered to induce hyperuricemic mice. The results demonstrated that the serum uric acid (Sur) level was significantly decreased by increasing the urinary uric acid (Uur) level and fractional excretion of urate (FEUA) with astilbin, related with suppressing role in meditation of Glucose transporter 9 (GLUT9), Human urate transporter 1 (URAT1) expression and up-regulation of ABCG2, Organic anion transporter 1/3 (OAT1/3) and Organic cation transporter 1 (OCT1). In addition, kidney function parameters, including serum creatinine (Scr) and blood urea nitrogen (BUN) were restored in astilbin-treated hyperuricemic rats. Further investigation indicated that astilbin prevented the renal damage against the expression of Thioredoxin-interacting protein (TXNIP) and its related inflammation signal pathway, including NLR pyrin domain-containing 3/Nuclear factor κB (NLRP3/NF-κB), which is associated with the up-regulation of interleukin-1β (IL-1β) and interleukin-18 (IL-18), and also presented a renal protective role by suppression oxidative stress. Moreover, astilbin inhibited activation of the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) cascade and over-expression of suppressor of cytokine signaling 3 (SOCS3) in the kidneys of potassium oxonate-induced mice. These findings provide potent evidence and therapeutic strategy for astilbin as a safe and promising compound in the development of a disease-modifying drug due to its function against hyperuricaemia and renal injury induced by potassium oxonate., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)