Search Results (30)

Xanthine oxidoreductase (XOR) is the only enzyme responsible for uric acid production and is essential for preventing gout. While XOR inhibitors effectively reduce serum urate levels, they also influence purine salvage and de novo pathways, as well as energy metabolism, raising concerns about metabolic adaptation and rebound effects upon treatment discontinuation. In this review, we outline the fundamental regulatory mechanisms of purine metabolism and summarize the mechanisms of action of XOR inhibitors and their associated metabolic effects with reference to XOR deficiency, type I xanthinuria. Furthermore, we discuss the impact of discontinuing XOR inhibitors and examine their potential for rebound. Full article

Non-communicable neurological disorders are the second leading cause of death, and their burden continues to increase as the world population grows and ages. Oxidative stress and inflammation are crucially implicated in the triggering and progression of multiple sclerosis, Alzheimer’s disease, amyotrophic lateral sclerosis, Huntington’s disease, Parkinson’s disease, and even stroke. In this narrative review, we examine the role of xanthine oxidoreductase (XOR) activities and products in all the above-cited neurological diseases. The redox imbalance responsible for oxidative stress could arise from excess reactive oxygen and nitrogen species resulting from the activities of XOR, as well as from the deficiency of its main product, uric acid (UA), which is the pivotal antioxidant system in the blood. In fact, with the exception of stroke, serum UA levels are inversely related to the onset and progression of these neurological disorders. The inverse correlation observed between the level of uricemia and the presence of neurological diseases suggests a neuroprotective role for UA. Oxidative stress and inflammation are also caused by ischemia and reperfusion, a condition in which XOR action has been recognized as a contributing factor to tissue damage. The findings reported in this review could be useful for addressing clinical decision-making and treatment optimization. Full article

The majority of naturally occurring mutations of the human gene XDH, are associated with reduced or completely absent xanthine oxidoreductase (XOR) activity, leading to a disease known as classical xanthinuria, which is due to the accumulation and excretion of xanthine in urine. Three types of classical xanthinuria have been identified: type I, characterised by XOR deficiency, type II, caused by XOR and aldehyde oxidase (AO) deficiency, and type III due to XOR, AO, and sulphite oxidase (SO) deficiency. Type I and II are considered rare autosomal recessive disorders, a condition where two copies of the mutated gene must be present to develop the disease or trait. In most cases, xanthinuria type I and II result to be asymptomatic, and only occasionally lead to renal failure due to urolithiasis caused by xanthine deposition. However, in the last 10–15 years, new observations have been made about the link between naturally occurring mutations and pathological phenotypes particularly pertinent to cardiovascular diseases (CVD). These links have been attributed to a genetically driven increase of XOR expression and activity that is responsible for what is thought to be damaging uric acid (UA) and reactive oxygen species (ROS) accumulation, nitric oxide (·NO) depletion and endothelial dysfunction. In this review, we discuss the importance of genetics for interindividual variability of XOR expression and activity while focusing mainly on those variants thought to be relevant for CVD. In addition, we discuss the potential exploitation of the genetically driven increase of XOR activity to deliver more beneficial bioavailable ·NO. Finally, we examine the effect that non-synonymous mutations have on the tertiary structure of the protein and consequently on its capacity to interact with glycosaminoglycans (GAGs) localised on the outer surface of endothelial cells. Full article

Xanthine oxidoreductase (XOR) is an enzyme involved in the oxidation of hypoxanthine and xanthine to uric acid. XOR has two isoforms: xanthine dehydrogenase and xanthine oxidase (XO). XO plays a major role in oxidative stress, causing the formation of reactive oxygen species. In the present study, we aimed to summarize the evidence on the association between XO and pregnancy complications. The PRISMA checklist guided the reporting of the data. We conducted systematic searches in the PubMed and Web of Science databases to identify all human studies investigating XO in pregnancy diseases up to June 2024. A total of 195 references have been identified and 14 studies were included. Most studies focused on women with PE and GD. Overall, all the included studies found a statistically significant increase in maternal, placental, and/or fetal XO levels, activity, or tissue expression in women with pregnancy complications, compared to those with uncomplicated pregnancies. Although promising, the quality and dimension of the included studies do not allow for a definitive answer to the question of whether XO may play a crucial role in pregnancy complications. Future studies are warranted to confirm if XO could represent a prognostic and therapeutic marker in pregnancy complications and their impact on long-term maternal and offspring cardiovascular health. Full article

In mammals, nitric oxide (NO) is generated either by the nitric oxide synthase (NOS) enzymes from arginine or by the reduction of nitrate to nitrite by tissue xanthine oxidoreductase (XOR) and the microbiome and further reducing nitrite to NO by XOR or several heme proteins. Previously, we reported that skeletal muscle acts as a large nitrate reservoir in mammals, and this nitrate reservoir is systemically, as well as locally, used to generate nitrite and NO. Here, we report identifying two additional nitrate storage organs—bone and skin. We used bolus of ingested ¹⁵N-labeled nitrate to trace its short-term fluxes and distribution among organs. At baseline conditions, the nitrate concentration in femur bone samples was 96 ± 63 nmol/g, scalp skin 56 ± 22 nmol/g, with gluteus muscle at 57 ± 39 nmol/g. In comparison, plasma and liver contained 34 ± 19 nmol/g and 15 ± 5 nmol/g of nitrate, respectively. Three hours after ¹⁵N-nitrate ingestion, its concentration significantly increased in all organs, exceeding the baseline levels in plasma, skin, bone, skeletal muscle, and in liver 5-, 2.4-, 2.4-, 2.1-, and 2-fold, respectively. As expected, nitrate reduction into nitrite was highest in liver but also substantial in skin and skeletal muscle, followed by the distribution of ¹⁵N-labeled nitrite. We believe that these results underline the major roles played by skeletal muscle, skin, and bone, the three largest organs in mammals, in maintaining NO homeostasis, especially via the nitrate–nitrite–NO pathway. Full article

Hyperuricemia (HUA), or elevated uric acid in the blood, has become more prevalent in recent years. Polyphenols, which are known to have good inhibitory activity on xanthine oxidoreductase (XOR), are effective in uric acid reduction. In this review, we address the structure–activity relationship of flavonoids that inhibit XOR activity from two perspectives: the key residues of XOR and the structural properties of flavonoids. Flavonoids’ inhibitory effect is enhanced by their hydroxyl, methoxy, and planar structures, whereas glycosylation dramatically reduces their activity. The flavonoid structure–activity relationship informed subsequent discussions of the changes that occur in polyphenols’ XOR inhibitory activity during their extraction, processing, gastrointestinal digestion, absorption, and interactions. Furthermore, gastrointestinal digestion and heat treatment during processing can boost the inhibition of XOR. Polyphenols with comparable structures may have a synergistic effect, and their synergy with allopurinol thus provides a promising future research direction. Full article

Hyperuricemia, i.e., increased plasma uric acid concentration, is a common problem in clinical practice, leading to gout or nephrolithiasis, and is associated with other disorders, such as metabolic syndrome, cardiovascular disease, and chronic renal disease. Xanthine oxidoreductase (XOR) is a critical rate-limiting enzyme involved in uric acid synthesis and a promising target for hyperuricemia therapy. However, XOR inhibitors currently face clinical problems such as a short half-life and side effects. Here, we found that specifically targeting liver Xor with GalNAc-siRNAs had a good therapeutic effect on hyperuricemia. First, siRNAs were designed to target various sites in the homologous region between Homo sapiens and Mus musculus Xor mRNA and were screened in primary mouse hepatocytes. Then, the siRNAs were modified to increase their stability in vivo and conjugated with GalNAc for liver-specific delivery. The effects of GalNAc-siRNAs were evaluated in three hyperuricemia mouse models, including potassium oxonate and hypoxanthine administration in WT and humanized XDH mice and Uox knockout mice. Febuxostat, a specific XOR inhibitor used for hyperuricemia treatment, was used as a positive control. Targeting liver Xor with GalNAc-siRNAs by subcutaneous administration reduced plasma uric acid levels, uric acid accumulation in the kidney, renal inflammation, and fibrosis, thereby alleviating kidney damage in hyperuricemia mouse models without hepatoxicity. The results demonstrated that targeting liver Xor with GalNAc-siRNAs was a promising strategy for hyperuricemia therapy. Full article

Xanthine Oxidoreductase (XOR) is a ubiquitous, essential enzyme responsible for the terminal steps of purine catabolism, ultimately producing uric acid that is eliminated by the kidneys. XOR is also a physiological source of superoxide ion, hydrogen peroxide, and nitric oxide, which can function as second messengers in the activation of various physiological pathways, as well as contribute to the development and the progression of chronic conditions including kidney diseases, which are increasing in prevalence worldwide. XOR activity can promote oxidative distress, endothelial dysfunction, and inflammation through the biological effects of reactive oxygen species; nitric oxide and uric acid are the major products of XOR activity. However, the complex relationship of these reactions in disease settings has long been debated, and the environmental influences and genetics remain largely unknown. In this review, we give an overview of the biochemistry, biology, environmental, and current clinical impact of XOR in the kidney. Finally, we highlight recent genetic studies linking XOR and risk for kidney disease, igniting enthusiasm for future biomarker development and novel therapeutic approaches targeting XOR. Full article

Upregulation of free radical-generating NADPH oxidases (NOX), xanthine oxidoreductase (XOR), and neutrophil infiltration-induced, NOX2-mediated respiratory burst contribute to renal ischemia–reperfusion injury (IRI), but their roles may depend on the severity of IRI. We investigated the role of NOX, XOR, and neutrophils in developing IRI of various severities. C57BL/6 and Mcl-1^ΔMyelo neutrophil-deficient mice were used. Oxidases were silenced by RNA interference (RNAi) or pharmacologically inhibited. Kidney function, morphology, immunohistochemistry and mRNA expression were assessed. After reperfusion, the expression of NOX enzymes and XOR increased until 6 h and from 15 h, respectively, while neutrophil infiltration was prominent from 3 h. NOX4 and XOR silencing or pharmacological XOR inhibition did not protect the kidney from IRI. Attenuation of NOX enzyme-induced oxidative stress by apocynin and neutrophil deficiency improved kidney function and ameliorated morphological damage after mild but not moderate/severe IRI. The IR-induced postischemic renal functional impairment (BUN, Lcn-2), tubular necrosis score, inflammation (TNF-α, F4/80), and decreases in the antioxidant enzyme (GPx3) mRNA expression were attenuated by both apocynin and neutrophil deficiency. Inhibition of NOX enzyme-induced oxidative stress or the lack of infiltration by NOX2-expressing neutrophils can attenuate reperfusion injury after mild but not moderate/severe renal IR. Full article

Taking into account the patient’s gender is the first step towards more precise and egalitarian medicine. The gender-related divergences observed in purine catabolism and their pathological consequences are good examples of gender medicine differences. Uric acid is produced by the activity of xanthine oxidoreductase (XOR). The serum levels of both XOR activity and uric acid differ physiologically between the genders, being higher in men than in women. Their higher levels have been associated with gout and hypertension, as well as with vascular, cardiac, renal, and metabolic diseases. The present review analyzes the gender-related differences in these pathological conditions in relation to increases in the serum levels of XOR and/or uric acid and the opportunity for gender-driven pharmacological treatment. Full article

Gout results from elevated serum urate (SU) levels, or hyperuricemia, and is a globally widespread and increasingly burdensome disease. Recent studies have illuminated the pathophysiology of gout/hyperuricemia and its epidemiology, diagnosis, treatment, and complications. The genetic involvement of urate transporters and enzymes is also proven. URAT1, a molecular therapeutic target for gout/hyperuricemia, was initially derived from research into hereditary renal hypouricemia (RHUC). RHUC is often accompanied by complications such as exercise-induced acute kidney injury, which indicates the key physiological role of uric acid. Several studies have also revealed its physiological role as both an anti-oxidant and a pro-oxidant, acting as both a scavenger and a generator of reactive oxygen species (ROSs). These discoveries have prompted research interest in SU and xanthine oxidoreductase (XOR), an enzyme that produces both urate and ROSs, as status or progression biomarkers of chronic kidney disease and cardiovascular disease. The notion of “the lower, the better” is therefore incorrect; a better understanding of uric acid handling and metabolism/transport comes from an awareness that excessively high and low levels both cause problems. We summarize here the current body of evidence, demonstrate that uric acid is much more than a metabolic waste product, and finally propose the novel disease concept of “dysuricemia” on the path toward “normouricemia”, or optimal SU level, to take advantage of the dual roles of uric acid. Our proposal should help to interpret the spectrum from hypouricemia to hyperuricemia/gout as a single disease category. Full article

Hyperuricemia is influenced by diet and can cause gout. Whether it is a potential risk factor for cardiovascular disease (CVD) remains controversial, and the mechanism is unclear. Similar to CVDs, gout attacks occur more frequently in the morning and at night. A possible reason for this is the diurnal variation in uric acid (UA), However, scientific data regarding this variation in patients with CVD are not available. Thus, we aimed to investigate diurnal variations in serum levels of UA and plasma levels of xanthine, hypoxanthine, and xanthine oxidoreductase (XOR) activity, which were measured at 18:00, 6:00, and 12:00 in male patients with coronary artery disease. Thirty eligible patients participated in the study. UA and xanthine levels significantly increased from 18:00 to 6:00 but significantly decreased from 6:00 to 12:00. By contrast, XOR activity significantly increased both from 18:00 to 6:00 and 6:00 to 12:00. Furthermore, the rates of increase in UA and xanthine levels from night to morning were significantly and positively correlated. In conclusion, UA and xanthine showed similar diurnal variations, whereas XOR activity showed different diurnal variations. The morning UA surge could be due to UA production. The mechanism involved XOR activity, but other factors were also considered. Full article

Proteoglycan 4 (PRG4) is a mucinous glycoprotein secreted by synovial fibroblasts and superficial zone chondrocytes, released into synovial fluid, and adsorbed on cartilage and synovial surfaces. PRG4′s roles include cartilage boundary lubrication, synovial homeostasis, immunomodulation, and suppression of inflammation. Gouty arthritis is mediated by monosodium urate (MSU) crystal phagocytosis by synovial macrophages, with NLRP3 inflammasome activation and IL-1β release. The phagocytic receptor CD44 mediates MSU crystal uptake by macrophages. By binding CD44, PRG4 limits MSU crystal uptake and downstream inflammation. PRG4/CD44 signaling is transduced by protein phosphatase 2A, which inhibits NF-κB, decreases xanthine oxidoreductase (XOR), urate production, and ROS-mediated IL-1β secretion. PRG4 also suppresses MSU crystal deposition in vitro. In contrast to PRG4, collagen type II (CII) alters MSU crystal morphology and promotes the macrophage uptake of MSU crystals. PRG4 deficiency, mediated by imbalance in PRG4-degrading phagocyte proteases and their inhibitors, was recently implicated in erosive gout, independent of hyperuricemia. Thus, dysregulated extracellular matrix homeostasis, including deficient PRG4 and increased CII release, may promote incident gout and progression to erosive tophaceous joint disease. PRG4 supplementation may offer a new therapeutic option for gout. Full article

Studies evaluating xanthine oxidoreductase (XOR) activities in comprehensive liver diseases are scarce, and different etiologies have previously been combined in groups for comparison. To accurately evaluate XOR activities in liver diseases, the plasma XOR activities in etiology-based comprehensive liver diseases were measured using a novel, sensitive, and accurate assay that is a combination of liquid chromatography and triple quadrupole mass spectrometry to detect [¹³C₂, ¹⁵N₂]uric acid using [¹³C₂, ¹⁵N₂]xanthine as a substrate. We also mainly evaluated the association between the plasma XOR activities and parameters of liver tests, purine metabolism-associated markers, oxidative stress markers, and an inflammation marker. In total, 329 patients and 32 controls were enrolled in our study. Plasma XOR activities were generally increased in liver diseases, especially in the active phase, such as in patients with hepatitis C virus RNA positivity, those with abnormal alanine transaminase (ALT) levels in autoimmune liver diseases, and uncured hepatocellular carcinoma patients. Plasma XOR activities were numerically highest in patients with acute hepatitis B. Plasma XOR activities were closely correlated with parameters of liver tests, especially serum ALT levels, regardless of etiology and plasma xanthine levels. Our results indicated that plasma XOR activity might reflect the active phase in various liver diseases. Full article

Uric acid (UA) forms monosodium urate (MSU) crystals to exert proinflammatory actions, thus causing gout arthritis, urolithiasis, kidney disease, and cardiovascular disease. UA is also one of the most potent antioxidants that suppresses oxidative stress. Hyper andhypouricemia are caused by genetic mutations or polymorphism. Hyperuricemia increases urinary UA concentration and is frequently associated with urolithiasis, which is augmented by low urinary pH. Renal hypouricemia (RHU) is associated with renal stones by increased level of urinary UA, which correlates with the impaired tubular reabsorption of UA. Hyperuricemia causes gout nephropathy, characterized by renal interstitium and tubular damage because MSU precipitates in the tubules. RHU is also frequently associated with tubular damage with elevated urinary beta2-microglobulin due to increased urinary UA concentration, which is related to impaired tubular UA reabsorption through URAT1. Hyperuricemia could induce renal arteriopathy and reduce renal blood flow, while increasing urinary albumin excretion, which is correlated with plasma xanthine oxidoreductase (XOR) activity. RHU is associated with exercise-induced kidney injury, since low levels of SUA could induce the vasoconstriction of the kidney and the enhanced urinary UA excretion could form intratubular precipitation. A U-shaped association of SUA with organ damage is observed in patients with kidney diseases related to impaired endothelial function. Under hyperuricemia, intracellular UA, MSU crystals, and XOR could reduce NO and activate several proinflammatory signals, impairing endothelial functions. Under hypouricemia, the genetic and pharmacological depletion of UA could impair the NO-dependent and independent endothelial functions, suggesting that RHU and secondary hypouricemia might be a risk factor for the loss of kidney functions. In order to protect kidney functions in hyperuricemic patients, the use of urate lowering agents could be recommended to target SUA below 6 mg/dL. In order to protect the kidney functions in RHU patients, hydration and urinary alkalization may be recommended, and in some cases an XOR inhibitor might be recommended in order to reduce oxidative stress. Full article