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

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Acta Pharmaceutica Sinica B 2024年第8期14卷 3591-3604页

作者： Juan Rong Chenxia Han Yan Huang Yiqin Wang Qi Qiu Manjiangcuo Wang Shisheng Wang Rui Wang Juqin Yang Xia Li Chenggong Hu Zhiyao Chen Lihui Deng Wei Huang Qing Xi Dan Du West China Center of Excellence for Pancreatitis Institute of Integrated Traditional Chinese and Western MedicineWest China Hospital/West China Medical SchoolSichuan UniversityChengdu 610041China State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China Advanced Mass Spectrometry Center Research Core FacilityFrontiers Science Center for Disease-related Molecular NetworkWest China HospitalSichuan UniversityChengdu 610213China Proteomics-Metabolomics Platform Research Core FacilityInstitutes for Systems GeneticsWest China HospitalSichuan UniversityChengdu 610093China Biobank West China HospitalSichuan UniversityChengdu 610093China West China School of Nursing Sichuan UniversityChengdu 610041China Department of Critical Care Medicine West China HospitalSichuan UniversityChengdu 610041China

Acute pancreatitis(AP)is a potentially fatal condition with no targeted treatment *** 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 ***,we aimed to re-evaluate whether XO is a target aggravating AP other than merely generating reactive oxygen species that trigger *** first revealed that XO expression and enzyme activity were significantly elevated in the serum and pancreas of necrotizing AP *** 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 ***,we observed that conditional Xdh overexpression aggravated pancreatic necrosis and *** 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)-***,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 *** 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.

关键词： xanthine oxidase inhibitor Multi-omics HIF-1a Necrotizing acute pancreatitis Lactate Therapeutic target NLRP3 Metabolic flux

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Linking uric acid metabolism to diabetic complications

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World Journal of Diabetes 2014年第6期5卷 787-795页

作者： Akifumi Kushiyama Kentaro Tanaka Shigeko Hara Shoji Kawazu Division of Diabetes and Metabolism The Institute for Adult DiseasesAsahi Life Foundation2-2-6

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.

关键词： Uric acid xanthine dehydrogenase/xanthine oxidase Diabetes mellitus Diabetic complications xanthine oxidase inhibitor Metabolism

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New synthesis route of febuxostat

New synthesis route of febuxostat

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中国化学会第27届学术年会

作者： Chuan-Fei Liu, Yan-Feng Dai*, Yuan Li Department of Chemistry, Nanchang University, 330031, Nanchang

＜正＞Febuxostat, an antipodagrics, was synthesized from 4-hydroxybenzoic acid by reactions of etherfication （protection）, ammoniation and thioformylation to give 4-Methoxythiobenzamide,

关键词： febuxostat anti gout drug xanthine oxidase inhibitor synthesis.

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