Mutations Associated with Functional Disorder of Xanthine Oxidoreductase and Hereditary Xanthinuria in Humans

Xanthine oxidoreductase (XOR) catalyzes the conversion of hypoxanthine to xanthine and xanthine to uric acid with concomitant reduction of either NAD⁺ or O₂. The enzyme is a target of drugs to treat hyperuricemia, gout and reactive oxygen-related diseases. Human diseases associated with genetically determined dysfunction of XOR are termed xanthinuria, because of the excretion of xanthine in urine. Xanthinuria is classified into two subtypes, type I and type II. Type I xanthinuria involves XOR deficiency due to genetic defect of XOR, whereas type II xanthinuria involves dual deficiency of XOR and aldehyde oxidase (AO, a molybdoflavo enzyme similar to XOR) due to genetic defect in the molybdenum cofactor sulfurase. Molybdenum cofactor deficiency is associated with triple deficiency of XOR, AO and sulfite oxidase, due to defective synthesis of molybdopterin, which is a precursor of molybdenum cofactor for all three enzymes. The present review focuses on mutation or chemical modification studies of mammalian XOR, as well as on XOR mutations identified in humans, aimed at understanding the reaction mechanism of XOR and the relevance of mutated XORs as models to estimate the possible side effects of clinical application of XOR inhibitors.     

Network Pharmacology Study on Morus alba L. Leaves: Pivotal Functions of Bioactives on RAS Signaling Pathway and Its Associated Target Proteins against Gout

M. alba L. is a valuable nutraceutical plant rich in potential bioactive compounds with promising anti-gouty arthritis. Here, we have explored bioactives, signaling pathways, and key proteins underlying the anti-gout activity of M. alba L. leaves for the first-time utilizing network pharmacology. Bioactives in M. alba L. leaves were detected through GC-MS (Gas Chromatography-Mass Spectrum) analysis and filtered by Lipinski’s rule. Target proteins connected to the filtered compounds and gout were selected from public databases. The overlapping target proteins between bioactives-interacted target proteins and gout-targeted proteins were identified using a Venn diagram. Bioactives-Proteins interactive networking for gout was analyzed to identify potential ligand-target and visualized the rich factor on the R package via the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway on STRING. Finally, a molecular docking test (MDT) between bioactives and target proteins was analyzed via AutoDock Vina. Gene Set Enrichment Analysis (GSEA) demonstrated that mechanisms of M. alba L. leaves against gout were connected to 17 signaling pathways on 26 compounds. AKT1 (AKT Serine/Threonine Kinase 1), γ-Tocopherol, and RAS signaling pathway were selected as a hub target, a key bioactive, and a hub signaling pathway, respectively. Furthermore, three main compounds (γ-Tocopherol, 4-Dehydroxy-N-(4,5-methylenedioxy-2-nitrobenzylidene) tyramine, and Lanosterol acetate) and three key target proteins—AKT1, PRKCA, and PLA2G2A associated with the RAS signaling pathway were noted for their highest affinity on MDT. The identified three key bioactives in M. alba L. leaves might contribute to recovering gouty condition by inactivating the RAS signaling pathway.     

食品中嘌呤含量分布的研究进展

目前国内外嘌呤检测方法不统一, 导致一些文献报道的同种食品中嘌呤分布数值出入较大。本文对食品中嘌呤检测的前处理方法、定量方法以及嘌呤含量分布研究现状进行综述分析, 以期为嘌呤检测技术发展提供借鉴。对于指导消费者合理膳食, 降低痛风发病率具有重要意义。     

黄嘌呤氧化酶抑制剂研究进展及发展前景

别嘌呤醇是治疗高尿酸血症及痛风的主要药物之一,可是该药物不但会引发皮肤炎症,还引其发热和多器官受损,甚至有引起死亡的报道。其安全性受到质疑。天然产物来源的黄嘌呤氧化酶抑制剂毒性小,安全性高,不易引起过敏反应且来源广,有的甚至可以用于日常饮食。本文对黄嘌呤氧化酶具有抑制作用的天然产物的研究进展及发展前景进行综述。     

The Role of ABCG2 in the Pathogenesis of Primary Hyperuricemia and Gout—An Update

Urate homeostasis in humans is a complex and highly heritable process that involves i.e., metabolic urate biosynthesis, renal urate reabsorption, as well as renal and extrarenal urate excretion. Importantly, disturbances in urate excretion are a common cause of hyperuricemia and gout. The majority of urate is eliminated by glomerular filtration in the kidney followed by an, as yet, not fully elucidated interplay of multiple transporters involved in the reabsorption or excretion of urate in the succeeding segments of the nephron. In this context, genome-wide association studies and subsequent functional analyses have identified the ATP-binding cassette (ABC) transporter ABCG2 as an important urate transporter and have highlighted the role of single nucleotide polymorphisms (SNPs) in the pathogenesis of reduced cellular urate efflux, hyperuricemia, and early-onset gout. Recent publications also suggest that ABCG2 is particularly involved in intestinal urate elimination and thus may represent an interesting new target for pharmacotherapeutic intervention in hyperuricemia and gout. In this review, we specifically address the involvement of ABCG2 in renal and extrarenal urate elimination. In addition, we will shed light on newly identified polymorphisms in ABCG2 associated with early-onset gout.     

原发性急性痛风性关节炎中药止痛效应的临床研究设计

依据痛风和疼痛评定的医学进展, 研究原发性急性痛风性关节炎中药止痛效应的临床评价设计技术要点, 包括研究目的, 诊断与影响因素, 治疗方案, 观察项目, 质量控制, 疗效评定, 统计分析要点。     

玉米须黄酮提取物对痛风性关节炎大鼠的影响

研究了玉米须黄酮提取物对尿酸钠所致大鼠痛风性关节炎的影响。给药组大鼠灌胃给予玉米须黄酮提取物(1 g/kg、0.5g/kg、0.25 g/kg),连续8天,空白及模型对照组灌胃给予等体积蒸馏水,第5天灌胃1小时后于模型及给药组大鼠右踝关节腔内注射尿酸钠溶液2.5 mg/m L,诱导痛风性关节炎的发生,72小时后测定大鼠踝关节肿胀度及血浆中白细胞介素1α(IL-1α)、白细胞介素6(IL-6)、肿瘤坏死因子α(TNF-α)、细胞间粘附分子1(ICAM-1)及基质金属蛋白酶1(MMP-1)的水平,并进行大鼠右踝关节病理组织学检查。与模型对照组比较,给予玉米须黄酮提取物后,其高、中剂量组(1 g/kg、0.5 g/kg)的踝关节肿胀度均明显降低(P0.01),血浆IL-1α、IL-6、TNF-α及血浆ICAM-1、MMP-1水平明显降低(P0.05),并且可以改善造模大鼠关节滑膜组织的病理改变。提示玉米须黄酮提取物具有较好的抗痛风性关节炎的作用。     

Management of hyperuricemia through dietary polyphenols as a natural medicament: A comprehensive review

Hyperuricemia, a condition due to high serum uric acid level and is notorious to health. It is considered to be a potent risk factor for gout and dramatically associated in the development of many chronic diseases such as malignant tumor, cardiovascular disorders and renal failure. Modern innovative medicinal and therapeutic interventions are underlying these days to combat hyperuricemia. Previously reported studies revealed the significant impact of dietary polyphenols (e.g. anthocyanins, phenolic acids, flavonoids etc.) against hyperurecemia disorder. Dietary plant polyphenols, unlike anti- hyperuricemic agents, are not reported to have any side effects in curing hyperuricemia. The current comprehensive review figure outs the use of dietary polyphenols as a natural remedy for the management of hyperuricemia. The sources, affiliated pathways, mode of actions and factors affecting their efficiency to prevent hyperuricemia are deeply discussed in this article. Additionally, limitations and suggestions regarding previously reported studies are also highlighted.     

治疗痛风和高尿酸血症药物研究进展

对急性痛风性关节炎的治疗,与常规剂量治疗方案相比,小剂量秋水仙碱或小剂量秋水仙碱+非甾体抗炎药治疗方案疗效相近,而安全性却大幅度提高。IL-1R拮抗剂阿那白滞素、利纳西普、康奈单抗等能有效缓解痛风急性期的症状,已成为第四类抗急性痛风的药物。别嘌呤醇的严重超敏反应综合征与肾功能、开始剂量、HLA-B*5801基因有关。非布司他、托匹司他、ulodesine、lesinurad、RDEA-3170、尿酸酶是近年来新型的降低尿酸药物。