Inhibition of xanthine oxidase alleviated pancreatic necrosis via HIF-1α-regulated LDHA and NLRP3 signaling pathway in acute pancreatitis

Acute pancreatitis(AP)is a potentially fatal condition with no targeted treatment options.Although inhibiting xanthine oxidase(XO)in the treatment of AP has been studied in several experimental models and clinical trials,whether XO is a target of AP and what its the main mechanism of action is remains unclear.Here,we aimed to re-evaluate whether XO is a target aggravating AP other than merely generating reactive oxygen species that trigger AP.We first revealed that XO expression and enzyme activity were significantly elevated in the serum and pancreas of necrotizing AP models.We also found that allopurinol and febuxostat,as purine-like and non-purine XO inhibitors,respectively,exhibited protective effects against pancreatic acinar cell death in vitro and pancreatic damage in vivo at different doses and treatment time points.Moreover,we observed that conditional Xdh overexpression aggravated pancreatic necrosis and severity.Further mechanism analysis showed that XO inhibition restored the hypoxia-inducible factor 1-alpha(HIF-1α)-regulated lactate dehydrogenase A(LDHA)and NOD-like receptor family pyrin domain containing 3(NLRP3)signaling pathways and reduced the enrichment of^(13)C_(6)-glucose to^(13)C_(3)-lactate.Lastly,we observed that clinical circulatory XO activity was significantly elevated in severe cases and correlated with C-reactive protein levels,while pancreatic XO and urate were also increased in severe AP patients.These results together indicated that proper inhibition of XO might be a promising therapeutic strategy for alleviating pancreatic necrosis and preventing progression of severe AP by downregulating HIF-1α-mediated LDHA and NLRP3 signaling pathways.

Febuxostat, a nonpurine selective inhibitor of xanthine oxidase： a promising medical therapy for chronic heart failure？

Heart failure is currently one of the most common and most cost-intensive of the chronic diseases The main cause of chronic heart failure （CHF） is the abnormalities of both cardiac contractile performance and myocardial energy metabolism. Elevated levels of reactive oxygen species （ROS） have been proposed to contribute to both of them. Xanthine oxidoreductase （XO） is a major source of ROS in the cardiovascular system. XO inhibitors （XOIs） have been the cornerstone of the clinical management of gout and conditions associated with hyperuricemia for several decades.

Linking uric acid metabolism to diabetic complications

Hyperuricemia have been thought to be caused by the ingestion of large amounts of purines, and prevention or treatment of hyperuricemia has intended to prevent gout. Xanthine dehydrogenase/xanthine oxidase(XDH/XO) is rate-limiting enzyme of uric acid generation, and allopurinol was developed as a uric acid(UA) generation inhibitor in the 1950 s and has been routinely used for gout prevention since then. Serum UA levels are an important risk factor of disease progression for various diseases, including those related to lifestyle. Recently, other UA generation inhibitors such as febuxostat and topiroxostat were launched. The emergence of these novel medications has promoted new research in the field. Lifestyle-related diseases, such as metabolic syndrome or type 2 diabetes mellitus, often have a common pathological foundation. As such, hyperuricemia is often present among these patients. Many in vitro and animal studies have implicated inflammation and oxidative stress in UA metabolism and vascular injury because XDH/XO act as one of the major source of reactive oxygen species Many studies on UA levels and associated diseases implicate involvement of UA generation in disease onset and/or progression. Interventional studies for UA generation, not UA excretion revealed XDH/XO can be the therapeutic target forvascular injury and renal dysfunction. In this review, the relationship between UA metabolism and diabetic complications is highlighted.