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Nanocapsules of oxalate oxidase for hyperoxaluria treatment

Nano Research 2018年第5期11卷 2682-2688页

作者： Ming Zhao Duo Xu Di Wu James W. Whittaker robert terkeltaub Yunfeng Lu Department of Chemical and Biomolecular Engineering University of California Los Angeles Los Angeles CA 90095 USA Division of Environmental and Biomolecular Systems Oregon Health and Sciences University Beaverton OR 97006-8921 USA Division of Rheumatology Allergy and Immunology San Diego VA Medical Center 3350 La Jolla Village Drive San Diego CA 92161 USA

Enzyme therapeutics have great potential for the treatment of systemic disorders such as urolithiasis and nephrocalcinosis, which are caused by the excessive accumulation of oxalate. However, exogenous enzymes have short half-lives in vivo and elicit high immunogenicity, which largely limit the therapeutic outcomes. Herein, we report a delivery strategy whereby therapeutic enzymes are encapsulated within a thin zwitterionic polymer shell to form enzyme nanocapsules. The strategy is exemplified by the encapsulation of oxalate oxidase （OxO） for the treatment of hyperoxaluria, because as-synthesized OxO nanocapsules have a prolonged blood circulation half-life and elicit reduced immunogenicity. Our design of enzyme nanocapsules that enable the systemic delivery of therapeutic enzymes can be extended to various biomedical applications.

关键词： enzyme therapeutics hyperoxaluria oxalate oxidase protein delivery long circulation nanomedicine

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Fatty acid oxidation-induced HIF-1α activation facilitates hepatic urate synthesis through upregulating NT5C2 and XDH

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Life Metabolism 2024年第5期3卷 17-31页

作者： Ningning Liang Xuan Yuan Lili Zhang Xia Shen Shanshan Zhong Luxiao Li Rui Li Xiaodong Xu Xin Chen Chunzhao Yin Shuyuan Guo Jing Ge Mingjiang Zhu Yongzhen Tao Shiting Chen Yongbing Qian Nicola Dalbeth Tony RMerriman robert terkeltaub Changgui Li Qiang Xia Huiyong Yin CAS Key Laboratory of Nutrition Metabolismand Food SafetyShanghai Institute of Nutrition and HealthChinese Academy of Sciences(CAS)Shanghai 200031China University of Chinese Academy of Sciences Beijing 100049China Department of Biomedical Sciences Jockey Club College of Veterinary Medicine and MedicineTung Biomedical Science CenterState Key Laboratory of Marine Pollution(SKLMP)The Shenzhen Research Institute and Futian Research InstituteCity University of Hong KongHong Kong 999077China Institute of Metabolic Diseases Qingdao UniversityQingdaoShandong 266003China Shandong Provincial Key Laboratory of Metabolic Diseases Qingdao Key Laboratory of GoutAffiliated Hospital of Qingdao University Medical CollegeQingdao UniversityQingdaoShandong 266071China School of Life Science and Technology ShanghaiTech UniversityShanghai 201210China Department of Liver Surgery Renji HospitalShanghai Jiao Tong University School of MedicineShanghai 200127China Department of Medicine Faculty of Medical and Health SciencesUniversity of AucklandAuckland 1142New Zealand Department of Biochemistry University of OtagoDunedin 9016New Zealand Division of Clinical Immunology and Rheumatology University of Alabama at BirminghamBirminghamAlabama 35294United States VA San Diego Healthcare System San DiegoLa JollaCA 92037United States School of Medicine University of California San DiegoLa JollaCA 92037United States

Dyslipidemia affects approximately half of all people with gout,and prior Mendelian randomization analysis suggested a causal role for elevated triglycerides in hyperuricemia(HU),but the underlying mechanisms remain *** hypothesize that dyslipi-demia promotes hepatic urate biosynthesis in HU and gout and fatty acid(FA)oxidation(FAO)drives this *** we devel-oped a targeted metabolomics to quantify major metabolites in purine metabolic pathway in the sera of a human cohort with HU,gout,and normaluricemic *** found that the levels of major purine metabolites and multiple FAs were significantly elevated in HU and gout groups compared to normouricemic controls,whereas hypoxathine showed opposite ***,the levels of multiple serum FAs were positively correlated with urate,xanthine,and inosine but negatively with hypoxanthine,which was also observed in a murine model of high-fat diet-induced *** a stable isotope-labeled metabolic flux assay,we discovered that exogenous hypoxanthine plays a key role in urate ***,FAO-induced hypoxia-inducible factor 1 alpha(HIF-1α)activation upregulated 5ʹ-nucleotidase II(NT5C2)and xanthine dehydrogenase(XDH)levels to facilitate hypox-anthine uptake from the blood to the liver and activation of urate *** findings were further supported by data in human hepatocytes and 50 paired serum and liver tissues from liver transplant ***,this study uncovers a mecha-nism by which FAO promotes hepatic urate synthesis by activating HIF-1α-NT5C2/XDH pathways,directly linking lipid metabo-lism to HU.

关键词： dyslipidemia hyperuricemia purine hypoxanthine metabolic flux

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