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Xanthine oxidoreductase has been implicated in cancer. Nonetheless, the role played by its two convertible forms, xanthine dehydrogenase (XDH) and oxidase (XO) during tumorigenesis is not understood. Here we produce XDH-stable and XO-locked knock-in (ki) mice to address this question. After tumor transfer, XO ki mice show strongly increased tumor growth compared to wild type (WT) and XDH ki mice. Hematopoietic XO expression is responsible for this effect. After macrophage depletion, tumor growth is reduced. Adoptive transfer of XO-ki macrophages in WT mice increases tumor growth. In vitro, XO ki macrophages produce higher levels of reactive oxygen species (ROS) responsible for the increased Tregs observed in the tumors. Blocking ROS in vivo slows down tumor growth. Collectively, these results indicate that the balance of XO/XDH plays an important role in immune surveillance of tumor development. Strategies that inhibit the XO form specifically may be valuable in controlling cancer growth. The roles of the convertible forms, xanthine dehydrogenase (XDH) and xanthine oxidase (XO) during tumorigenesis is not known. Here, the authors develop XDH-stable and XO-locked knock-in (ki) mice and show increased tumor growth in XO ki mice, via macrophage-mediated immunoregulatory responses.

Xanthine oxidoreductase (XOR), which is widely distributed from humans to bacteria, has a key role in purine catabolism, catalyzing two steps of sequential hydroxylation from hypoxanthine to xanthine and from xanthine to urate at its molybdenum cofactor (Moco). Human XOR is considered to be a target of drugs not only for therapy of hyperuricemia and gout, but also potentially for a wide variety of other diseases. In this review, we focus on studies of XOR inhibitors and their implications for understanding the chemical nature and reaction mechanism of the Moco active site of XOR. We also discuss further experimental or clinical studies that would be helpful to clarify remaining issues.

Overexpression of phosphodiesterase 5 (PDE-5) presents a compelling target for the therapy of erectile dysfunction. Sildenafil and other conventional PDE-5 inhibitors may lead to adverse effects, including visual disturbances and migraines. Therefore, the investigation of novel inhibitors with enhanced safety profiles is imperative. This research employed a computational drug repurposing approach to assess US-FDA-approved xanthine derivatives (XDs) for their efficacy in targeting PDE-5. XDs exhibit a favorable affinity for the active site of the PDE-5 receptor, with binding scores between −10.0 kcal/mol and −6.3 kcal/mol for linagliptin and theobromine, respectively. The top-ranked docked Xds then underwent 300-nanosecond molecular dynamics simulations. Linagliptin demonstrated greater stability in the binding pocket (RMSD = 1.60 ± 0.34) compared to the typical inhibitor sildenafil (RMSD = 1.70 ± 0.27). The findings were corroborated by MM-PBSA calculation, which showed that linagliptin’s binding free energy of −45.6 ± 4.3 kcal/mol comparable with sildenafil’s −49.0 ± 3.1 kcal/mol. This value is notably higher than that of the deprotonated form of sildenafil, which is present at a 37.06% ratio at physiological pH 7.4. Additionally, we used per-residue energy decomposition to identify crucial residues for PDE-5 activity and thoroughly investigated hydrogen bond occupancy. This study points outthe potential of linagliptin as a PDE-5 inhibitor, paving the way for the development of a safe treatment for erectile dysfunction.

Xanthine dehydrogenase (XDH) is a molybdenum cofactor (Moco) requiring enzyme that catabolizes hypoxanthine into xanthine and xanthine into uric acid, the final steps in purine catabolism. Human patients with mutations in XDH develop xanthinuria which can lead to xanthine stones in the kidney, recurrent urinary tract infections, and renal failure. Currently, there are no therapies for treating human XDH deficiency. Thus, understanding mechanisms that maintain purine homeostasis is an important goal of human health. Here, we used the nematode Caenorhabditis   elegans to model human XDH deficiency using two clinically relevant paradigms: Moco deficiency or loss-of-function mutations in xdh-1 , the C. elegans ortholog of XDH . Both Moco deficiency and xdh-1 loss of function caused the formation of autofluorescent xanthine stones in C. elegans . Surprisingly, only 2% of xdh-1 null mutant C. elegans developed a xanthine stone, suggesting additional pathways may regulate this process. To uncover such pathways, we performed a forward genetic screen for mutations that enhance the penetrance of xanthine stone formation in xdh-1 null mutant C. elegans . We isolated multiple loss-of-function mutations in the gene sulp-4 which encodes a sulfate permease homologous to human SLC26 anion exchange proteins. We demonstrated that SULP-4 acts cell-nonautonomously in the excretory cell to limit xanthine stone accumulation. Interestingly, sulp-4 mutant phenotypes were suppressed by mutations in genes that encode for cystathionase ( cth-2) or cysteine dioxygenase ( cdo-1 ), members of the sulfur amino acid catabolism pathway required for production of sulfate, a substrate of SULP-4. We propose that sulfate accumulation caused by sulp-4 loss of function promotes xanthine stone accumulation. We speculate that sulfate accumulation causes osmotic imbalance, creating conditions in the intestinal lumen that favor xanthine stone accumulation. Supporting this model, a mutation in osm-8 that constitutively activates the osmotic stress response also promoted xanthine stone accumulation in an xdh-1 mutant background. Thus, our work establishes a C. elegans model for human XDH deficiency and identifies the sulfate permease sulp-4 as a critical player controlling xanthine stone accumulation.

Gout is a common metabolic disorder caused by hyperuricaemia, with xanthine oxidase (XO) playing a key role in uric acid production. Food-derived XO inhibitors are therefore of interest as candidate chemotypes, although any nutraceutical application will require in-vivo validation. In this study, we developed an integrated in-silico workflow that combines machine learning, molecular docking, and molecular dynamics (MD) to prioritize potential inhibitors. From a library of 3,142 medicine–food homology compounds, we trained multiple fingerprint–algorithm classifiers; the topological-torsion Random Forest (TT-RF) model performed best, achieving an AUC of 0.992 and a precision of 0.98 on a held-out test set. Applying this model yielded 128 high-confidence hits, ten of which showed docking scores ≤ –9.0 kcal/mol. Subsequent 200-ns MD simulations indicated that luteolin-7-glucuronide, 5,4′-dihydroxyflavone, and uralenol form stable, compact complexes with XO. In-vitro assays further confirmed XO inhibition, with IC50 values of 26.15, 39.06, and 34.64 µM, respectively, and negligible cytotoxicity in HepG2 cells up to 100 µM. Together, these results identify food-derived compounds with reproducible in-vitro XO inhibition. Their significance for gout management remains to be established in in-vivo studies. More broadly, this study illustrates a scalable framework for natural-product–based inhibitor discovery that can guide future preclinical validation.

Pharmacological studies revealed that the Balanophora species contains diverse phytochemicals which enable interesting biological activities and emphasize their pharmaceutical relevance. Previously, we identified significant xanthine oxidase (XO) inhibitory activity from extracts of the two Balanophora spp. ( Balanophora subcupularis P.C. Tam and Balanophora tobiracola Makino). However, the specific compounds responsible for this activity remain unidentified so far. Thus, in the present study, we focused on elucidating the compounds inducing the XO inhibitory effect of extracts from Balanophora species. Therefore, a combination of advanced liquid chromatography and mass spectrometry (LC-QToF-HRMS), virtual screening using machine learning (ML) models, and molecular docking simulation was applied. Using LC-QToF-HRMS, 23 and 21 compounds were identified in the ethyl acetate fractions of B. subcupularis and B. tobiracola , respectively. Next, a curated dataset of natural and synthetic compounds with known XO inhibitory activity was employed to train several ML models. Adducing five selected ML models, the virtual screening process identified the potentially active compounds 1-(3,4-dihydroxyphenyl)-6,7-dihydroxy-1,2-dihydro-2,3-naphthalenedicarboxylic acid, taxifolin, and 1- O -caffeoyl-6- O -(S)-brevifolincarboxyl- β -D-glucopyranose. All the compounds found in the two Balanophora spp. underwent docking simulations, in which MTE, FES, and AFH were retained in the active site of XO, ensuring reliable re-docking results. Finally, taxifolin emerged as the most promising novel XO inhibitor, demonstrating greater potential than the established drug allopurinol, as supported by both the virtual screening nomination and docking simuation. These findings contribute to the development of natural XO inhibitors and may open new opportunities for gout treatment and uric acid level control.

In a double-blind trial, patients with type 1 diabetes and early-to-moderate diabetic kidney disease were randomly assigned to receive allopurinol, which may slow the decline in the glomerular filtration rate, or placebo. There were no clinically meaningful benefits of serum urate reduction on kidney outcomes with allopurinol therapy.

Activation of the NLRP3 inflammasome by microbial ligands or tissue damage requires intracellular generation of reactive oxygen species (ROS). We present evidence that macrophage secretion of IL1β upon stimulation with ATP, crystals or LPS is mediated by a rapid increase in the activity of xanthine oxidase (XO), the oxidized form of xanthine dehydrogenase, resulting in the formation of uric acid as well as ROS. We show that XO-derived ROS, but not uric acid, is the trigger for IL1β release and that XO blockade results in impaired IL1β and caspase1 secretion. XO is localized to both cytoplasmic and mitochondrial compartments and acts upstream to the PI3K–AKT signalling pathway that results in mitochondrial ROS generation. This pathway represents a mechanism for regulating NLRP3 inflammasome activation that may have therapeutic implications in inflammatory diseases. Activation of NLRP3 inflammasome requires generation of reactive oxygen species. Here the authors show that microbial or tissue damage-derived signals activate xanthine oxidase, which serves as a critical source of reactive oxygen species for inflammasome activation in macrophages.

This randomized trial assessed whether urate-lowering treatment with allopurinol could attenuate eGFR decline in at-risk patients with stage 3 or 4 chronic kidney disease. Allopurinol did not slow the decline in eGFR as compared with placebo.

In most patients with type 1 xanthinuria caused by mutations in the xanthine dehydrogenase gene ( XDH ), no clinical complications, except for urinary stones, are observed. In contrast, all Xdh (− / −) mice die due to renal failure before reaching adulthood at 8 weeks of age. Hypoxanthine or xanthine levels become excessive and thus toxic in Xdh (− / −) mice because enhancing the activity of hypoxanthine phosphoribosyl transferase (HPRT), which is an enzyme that uses hypoxanthine as a substrate, slightly increases the life span of these mice. In this study, we targeted the mouse intestinal sodium-dependent nucleobase transporter (SNBT) gene ( Slc23a4 ), which is a pseudogene in humans. Hprt (high) Xdh (− / −) Slc23a4 (− / −) mice had a longer life span and reached adulthood. The urinary xanthine excretion of these mice was 20-fold greater than that of patients with type 1 xanthinuria. The urinary hypoxanthine/xanthine ratio of Hprt (high) Xdh (− / −) Slc23a4 (− / −) mice was lower than that of patients with type 1 xanthinuria. Hprt (high) Xdh (− / −) Slc23a4 (− / −) mice exhibited renal impairment, accompanied by high plasma creatinine levels and anemia. Moreover, female Hprt (high) Xdh (− / −) Slc23a4 (− / −) mice produced offspring that did not survive. In conclusion, for the first time, we established that Xdh (− / −) mice survive to adulthood.