Xanthine oxidoreductase (XOR) is an enzyme that catalyzes hypoxanthine to xanthine and xanthine to uric acid, respectively. However, the underlying mechanisms of increased plasma XOR and its pathological roles in systemic diseases, such as atherosclerosis, are not fully understood. In this study, we found that changes in plasma XOR activity after bariatric surgery closely associated with those in liver enzymes, but not with those in BMI. In a mouse model of nonalcoholic fatty liver disease/steatohepatitis (NAFLD/NASH), plasma XOR activity markedly increased. Besides, purine catabolism was accelerated in the plasma per se of NASH mice and human patients with high XOR activity. In our NASH mice, we observed an increased vascular neointima formation consisting of dedifferentiated vascular smooth muscle cells (SMCs), which was significantly attenuated by topiroxostat, a selective XOR inhibitor. In vitro, human liver S9–derived XOR promoted proliferation of SMCs with phenotypic modulation and induced ROS production by catabolizing hypoxanthine released from human endothelial cells. Collectively, the results from human and mouse models suggest that increased plasma XOR activity, mainly explained by excess hepatic leakage, was involved in the pathogenesis of vascular injury, especially in NAFLD/NASH conditions.

Plasma xanthine oxidoreductase (XOR) activity is high in metabolic disorders such as diabetic mellitus, obesity, or overweight. Thus, this study investigated whether the XOR inhibitor, topiroxostat, affected body weight. Male db/db mice were fed standard diets with or without topiroxostat for 4 weeks. Body weight and food intake were constantly monitored, along with monitoring plasma biochemical markers, including insulin and XOR activity. Additionally, hepatic hypoxanthine and XOR activity were also documented. Single regression analysis was performed to determine the mechanism. Topiroxostat treatment suppressed weight gain relative to the vehicle without any impact on food intake. However, the weight of fat pads and hepatic and muscle triglyceride content did not change. Topiroxostat decreased the plasma uric acid and increased hepatic hypoxanthine in response to the inhibition of XOR activity. Plasma ketone body and free fatty acid were also increased. Moreover, fat weight was weakly associated with plasma XOR activity in the diabetic state and was negatively associated with ketone body by topiroxostat. These results suggested that topiroxostat amplified the burning of lipids and the salvage pathway, resulting in predisposing the body toward catabolism. The inhibition of plasma XOR activity may contribute to weight loss.

Hyperuricemia causes gout and has also been associated with metabolic syndrome and cardiovascular disease. Uric acid-lowering drugs (ULDs) are used to reduce uric acid levels for the treatment of hyperuricemia and gout. However, there is a lack of robust and real-world data on the history and treatment of patients with newly diagnosed hyperuricemia or gout in Japan. This retrospective, longitudinal, historical cohort study determined the characteristics of patients with hyperuricemia and/or gout, and prescription of, and adherence to, ULDs using data from the JMDC Claims Database. The primary evaluation population included 64 677 patients with newly diagnosed hyperuricemia and/or gout. Of these, only 26 501 (41.0%) had a prescription for ULDs at diagnosis. Even when ULDs were prescribed, the persistence rate of prescriptions declined over time, with a 54.4% persistence rate for ULDs at 12 months after the index diagnosis. In subgroups of patients with or without hypertension and diabetes, the rate of ULD prescription continuation was significantly higher in those with comorbidities than in those without (76.8% vs. 42.6% in those with vs. without hypertension, and 78.7% vs. 52.2% in those with vs. without diabetes). These finding suggest that therapeutic interventions to lower serum uric acid levels are under-utilized for patients with newly diagnosed hyperuricemia and/or gout in Japan.

Background: The effects of uric acid (UA)-lowering therapy with xanthine oxidoreductase (XOR) inhibitors on the development of cardiovascular diseases remain controversial. Based on recent findings that plasma XOR activity increased in liver disease conditions, we conducted a sub-analysis of the BEYOND-UA study to examine the differential effects of topiroxostat on arterial stiffness based on liver function in hyperuricemic individuals with hypertension. Methods: Sixty-three subjects treated with topiroxostat were grouped according to baseline alanine aminotransferase (ALT) levels (above or below cut-off values of 22, 30, or 40 U/L). The primary endpoint was changes in the cardio-ankle vascular index (CAVI) from baseline to 24 weeks. Results: Significant reductions in CAVI during topiroxostat therapy occurred in subjects with baseline ALT ≥30 U/L or ≥40 U/L, and significant between-group differences were detected. Brachial-ankle pulse wave velocity significantly decreased in the ALT-high groups at all cut-off values. Reductions in morning home blood pressure and serum UA were similar regardless of the baseline ALT level. For eleven subjects with available data, ALT-high groups showed high plasma XOR activity, which was significantly suppressed by topiroxostat. Conclusions: Topiroxostat improved arterial stiffness parameters in hyperuricemic patients with liver dysfunction, which might be related to its inhibitory effect on plasma XOR.

Blood levels of hypoxanthine (HX) have been suggested as potential biomarkers associated with intramuscular metabolic dynamics in response to exercise. This pilot randomized crossover trial (UMIN000036520) aimed to investigate the changes in plasma HX after whole-body vibration exercise (WBVE) and their relationships with body composition and muscle-related parameters, enrolling eighteen healthy male volunteers. In the WBVE-alone intervention, the study subjects performed 20-min of WBVE. In the OGTT → WBVE intervention, a 75-g oral glucose load (OGL) was administered 30 min prior to the start of the WBVE intervention. Blood samples were collected before the start and 10 min after the end of WBVE in both interventions. WBVE resulted in a significant increase in plasma HX levels, which was accompanied by increased blood ammonia, pyruvic acid, and lactic acid levels. The HX increase following WBVE was suppressed by prior OGL. In the WBVE-alone intervention, there were no significant correlations between the post-WBVE changes in plasma HX (ΔHX) levels and any of the clinical parameters. On the other hand, in the OGTT → WBVE intervention, ΔHX showed significant negative correlations with muscle mass (ρ = –0.62, p = 0.01), strength (ρ = –0.71, p = 0.005), and muscle quality (ρ = –0.81, p = 0.0007) in the legs. In conclusion, these findings suggest possible associations between post-WBVE increases in plasma HX levels and muscle status, particularly under the glucose-supplemented condition. The measurement of plasma HX concentrations following WBVE may have clinical applications in the identification of high-risk populations for sarcopenia.

Objectives: Reactive oxygen species generated by xanthine oxidoreductase (XOR) are associated with the progression of atherosclerosis. However, changes in plasma XOR (pXOR) activity after percutaneous coronary intervention (PCI) for stable coronary artery disease (CAD) remains unknown. Methods: Herein, we compared the change in the pXOR activity in patients undergoing PCI with that in patients undergoing coronary angiography (CAG) and further evaluated the relation between changes in pXOR activity and in-hospital and long-term outcomes of patients undergoing PCI. The pXOR activity of 80 consecutive patients who underwent PCI and 25 patients who underwent CAG during the hospitalization was analyzed daily. The percentage changes from baseline regulated time interval was evaluated. Results: We found that although pXOR activity decreased after PCI, and remained low until discharge, no significant changes were observed in patients undergoing CAG. Furthermore, among the patients undergoing PCI, those who experienced in-hospital adverse events, had a higher percentage of pXOR reduction 3 days after PCI. There was no association between these changes and long-term events. Conclusions: A significant change in pXOR activity was observed in patients undergoing PCI than in patients undergoing CAG, and there seems to be a correlation between the in-hospital outcomes and the percentage reduction from baseline in pXOR activity.