重组尿酸氧化酶对动物高尿酸血症的治疗作用及安全性研究

目的探索重组尿酸氧化酶对动物高尿酸血症的治疗作用,并评价其安全性。方法通过给予乙胺丁醇和腺嘌岭或黄嘌呤,建立小鼠高尿酸血症模型,并考察尿酸氧化酶的降血清尿酸作用：选取猕猴进行3月长期毒性研究,使用酶联免疫吸附试验（ELISA）检测猕猴毒性试验给药结束及恢复期后抗体的产生情况。结果重组尿酸氧化酶可显著降低小鼠的尿酸水平;猕猴的长期毒性试验未发现与药物相关的明显毒性反应;猕猴体内检获相关抗体,恢复期后产生抗体的比例大大降低。结论重组尿酸氧化酶对动物高尿酸血症具有显著治疗作用,猕猴的安全剂量大于3．2mg／kg。     

痛风颗粒各部位对高尿酸血症大鼠尿酸和黄嘌呤氧化酶活性的影响

目的 通过观察痛风颗粒各部位对高尿酸血症大鼠血尿酸、尿尿酸、血黄嘌呤氧化酶活性和肝脏黄嘌呤氧化酶活性的影响,探讨其治疗痛风的物质基础和机制.方法 以腺嘌呤合乙胺丁醇法诱导大鼠高尿酸血症模型,分别用磷钨酸法和酶比色法检测尿酸和黄嘌呤氧化酶的含量.结果 黄酮类成分在降尿酸和抑制黄嘌呤氧化酶活性上均起主要作用;生物碱类成分对尿中尿酸的排泄和血清黄嘌呤氧化酶活性的抑制起较重要作用,有机酸类成分均未表现出明显作用;全方和有效部位组合有明显的降尿酸和抑制黄嘌呤氧化酶活性的作用.结论 黄酮类、生物碱和有机酸类有效部位组合后的药效与处方药一致,是该处方的有效部位群,对高尿酸血症模型大鼠表现出的降尿酸和抑制黄嘌呤氧化酶活性的作用最为显著.     

南极磷虾肽改善高尿酸血症机制研究

目的 探究南极磷虾肽(AKP)对于高尿酸血症模型小鼠的降尿酸功效及其作用机制.方法 采用高效液相色谱(HPLC)法体外筛选出具尿酸合成关键限速酶—黄嘌呤氧化酶(Xanthine oxidase,XOD)抑制活性的AKP,体内动物实验验证AKP的降尿酸活性.雄性Balb/c小鼠采用高嘌呤饲料(25％酵母浸粉)喂养联合腹腔...     

桑抹茶对高尿酸血症模型大鼠血尿酸水平及肠道菌群的影响

目的 观察桑抹茶对高尿酸血症模型大鼠血清尿酸及肠道菌群的调节作用。方法 采用高嘌呤饲料喂养复制高尿酸血症大鼠模型,同时给予桑抹茶干预,于实验期末,用全自动生化仪检测血清尿酸、肌酐、尿素氮水平,ELISA法检测血清及肝组织黄嘌呤氧化酶活性和细菌内毒素水平;收集粪便,提取肠道菌群DNA,进行16S rRNA生物信息学分析。结果 桑抹茶干预能显著降低模型大鼠血清尿酸、肌酐、尿素氮水平及血清、肝组织黄嘌呤氧化酶活性;增加肠道乳杆菌比例,降低血清内毒素水平。RAD结果显示,肠道菌群分类水平与血尿酸、黄嘌呤氧化酶活性相关。结论 桑抹茶具有降尿酸作用,该作用可能与调节肠道菌群,降低血清内毒素水平,抑制黄嘌呤氧化酶活性有关。     

Comparative effects of green and black tea extracts on lowering serum uric acid in hyperuricemic mice

Context: Tea (Camellia sinensis (L.) Kuntze [Theaceae]) is used to induce urination and inducing nervous excitation. Green and black teas have multifarious physiological functions. The different effects of green and black tea aqueous extracts (GTEs and BTEs) on hyperuricemia are not definitely reported.

Objective: The different effects of GTEs and BTEs on lowering serum uric acid (UA) in hyperuricemic mice were determined.

Materials and methods: Kunming mice were divided into nine groups (n?=?6/each group). GTEs and BTEs at the doses of 0.5, 1 and 2?g/kg were orally administrated to mice for seven days, respectively. Hepatic xanthine oxidase (XOD) and adenosine deaminase (ADA) activities as mechanisms of actions were assessed.

Results: Research indicated that the LD₅₀ of tea extract is greater than 2?g/kg in mice. UA levels were suppressed significantly with dose-dependent treatment of 0.5, 1 and 2?g/kg BTEs (up to 25.5%, 28.7% and 29.8%, respectively); the serum UA levels were decreased by GTEs but not significant. The activities of XOD and ADA in high dose (2?g/kg) groups of both GTEs and BTEs were notably lower than those of the model group.

Discussion and conclusions: The results suggested that both GTEs and BTEs have hypouricaemic and renal protective effects on hyperuricemic mice and the latter one was better. Our study sheds light on the research and development of anti-hyperuricemic functional foods and drugs from tea.     

摄食海参皂苷对小鼠高尿酸血症的影响

目的研究海参皂苷对酵母浸粉诱导的高尿酸血症小鼠的尿酸代谢及相关酶活性的影响。方法将24只♂昆明种小鼠随机分为正常组、模型组、皂苷低、高剂量组。采用口服酵母浸粉进行造模,连续喂饲14 d,分别测定小鼠血清尿酸(uric acid,UA)、肌酐(creatinine,Cr)、尿素氮(blood ureanitrogen,BUN)水平,以及肝脏黄嘌呤氧化酶(xanthine oxi-dase,XOD)、腺苷脱氨酶(adenosine deaminase,ADA)活性。结果喂养14 d后,海参皂苷高、低剂量组血清尿酸水平分别较对照组降低53.1%与55.6%(均P<0.01),肝脏XOD及ADA的活性明显受到抑制,XOD活性分别降低26.3%与28.6%(均P<0.01),ADA活性分别降低24.4%(P<0.05)与34.0%(P<0.01),血清肌酐与尿素氮无变化。结论海参皂苷对酵母浸粉诱导的高尿酸血症有明显的改善作用,其机制与抑制了肝脏XOD和ADA活性有关。     

金苓痛风舒微丸对高尿酸血症小鼠血尿酸、肌酐、尿素氮及黄嘌呤氧化酶活性的影响

目的研究金苓痛风舒微丸对高尿酸血症小鼠的血尿酸(blood uric acid,BUA)、肌酐(creatinine,Cr)、尿素氮(blood urea nitrogen,BUN)、黄嘌呤氧化酶(xanthine oxidase,XOD)活性的影响,探讨其治疗痛风的机制。方法采用化学诱导剂氧嗪酸钾盐腹腔注射建立高尿酸血症小鼠模型,药物组分别灌服不同剂量金苓痛风舒微丸,1日1次,连续7d。末次给药1h后,取血,分离血清,采用ELISA法测定小鼠血清BUA、Cr和BUN;取肝脏组织检测XOD的活性。结果金苓痛风舒微丸高、中剂量能显著地降低高尿酸血症小鼠BUA、Cr和BUN的水平(P<0.01),高剂量显著抑制肝脏XOD的活性(P<0.01),中剂量也可明显降低XOD活性(P<0.05)。结论金苓痛风舒微丸的作用机制可能是通过增强肾血流量以及抑制尿酸的分解协同完成的。     

短穗兔耳草提取物对高尿酸血症小鼠肾脏保护作用研究

目的 研究短穗兔耳草提取物对高尿酸血症小鼠肾脏有无保护作用。方法 以氧嗪酸钾盐诱导小鼠高尿酸血症模型为实验系统,通过检测血清尿酸和黄嘌呤氧化酶含量和肾脏病理病变等指标,评价短穗兔耳草提取物对高尿酸血症小鼠肾脏的保护作用。结果 短穗兔耳草可显著降低模型大鼠血清、尿酸和黄嘌呤氧化酶含量, 改善了小鼠肾脏结构的变化。结论 短穗兔耳草具有降尿酸活性及肾脏保护作用。     

Exploration on the establishment of animal models for hyperuricemia and the application of traditional Chinese medicine

OBJECTIVE In recent years,the frequency of hyperuricemia has gradually risen along with the improvement of living standards,the irregular of diet and overfeeding greasy and surfeit flavor.However,hyperuricemia is a disorder of purine metabolism,and is strongly associated with insulin resistance and abnormal glucose metabolism.It is important to obtain a more stable and sustained animal model for the efficacy evaluation of traditional Chinese medicine(TCM).METHODS To manufacture the rodent model of hyperuricemia,the theory of increasing the source of the uric acid,reducing uric acid excretion and inhibiting uricase were used.We observed the influence on the serum uric acid and other indicators of rats induced by some factors:the lipid emulsion,high purine diet,beer with sugar,beer with sugar and high purine,and so on.Then we choose one of the stable and sustained animal models,studying the effects of Plo.E(which extracted from a TCM)on modulating the level of serum uric acid and the preliminary mechanism in this abstract.RESULTS ① At the 2nd week,the level of serum UA,BUN,Cr,TC,LDL-c of rats in the lipid emulsion group raised significantly.② At the 6th weeks,the serum UA in both the high purine diet group and lipid emulsion group raised obviously.③ The effects of Plo.E on hyperuricemia rats induced by high purine diet:After 8d administration,the Plo.E(three dosages)can reduce the UA level,and the middle and low dosages can reduce the TG level.After 25 dadministration,Plo.E can reduce the plasma viscosity,UA,TG,the whole blood viscosity level,the high dosage also can reduce the TC level.CONCLUSION The rats induced by the high purine diet and lipid emulsion can raised the serum UA obviously,while the way of lipid emulsion is earlier and more stable.Plo.E has a therapeutic effect on hyperuricemia,with an activity of reducing plasma viscosity and blood lipid.The above models conform to the pathogenesis of humans,can be used to study the causes and pathogenesis of hyperuricemia complicating metabolic disorder and the related treatment drug screening.     

尿酸酶-过氧化氢酶复合纳米脂质体对高尿酸血症小鼠的治疗作用

目的 考察硼酸-硼砂缓冲液制备的尿酸酶(UA)-过氧化氢酶(CA)复合纳米脂质体(UCLP)对高尿酸血症小鼠的治疗作用.方法 采用pH8.5的硼酸-硼砂缓冲液,运用逆向蒸发法制备UCLP,并考察测定UCLP中UA的最适温度和最适pH;建立小鼠高尿酸血症模型后,给予UCLP治疗,用相应试剂盒测定小鼠体内尿酸和过氧化氢的浓度.结果 UCLP中UA的最适温度为40℃,最适pH为8.0;UCLP组小鼠体内尿酸和过氧化氢的浓度均较UA组低.结论 UCLP能有效降低高尿酸血症小鼠体内的尿酸水平,同时降低体内过氧化氢的浓度.     

Xanthine oxidase inhibitory activity and hypouricemia effect of propolis in rats

The xanthine oxidase (XOD) inhibitory activity of propolis from China and Brazil was measured. The propolis from both place were seen to have XOD inhibitory activity. However, a stronger tendency was shown in the propolis from China. The compounds in each the propolis were measured quantitatively. A great deal of chrysin, galangin, and caffeic acid phenetyl ester were found in the propolis from China, an abundance of p-coumaric acid and artepillin C in the propolis from Brazil. Therefore it was revealed that the propolis compounds are very different depending on their place of origin. The XOD inhibitory activity of these five compounds was measured. Caffeic acid phenetyl ester had the strongest activity, with chrysin and galangin next; p-coumaric acid and artepillin C showed weak XOD inhibitory activity. We evaluated the hypouricemic effect of propolis from China on hyperuricemia induced by the uricase inhibitor, oxonic acid (500 mg/kg p.o., 1 h before the test drugs), and measured plasma uric acid values in rats. Oral propolis had a hypouricemic effect 2 h after its administration to oxonate-pretreated rats. These results suggested that a continuous intake of propolis may be effective for the prevention and the treatment of gout and hyperuricemia.     

Combined anti-hyperuricemia effect of Di.E and Gpm.E on hyperuricemia rats induced by high-purine diet

OBJECTIVE Di.E and Gpm.E were separately extracted from two kinds of traditional Chinese medicine.The aim of this research is to investigate the combined anti-hyperuricemia effect of Di.E and Gpm.E on hyperuricemia rats induced by high-purine diet,and to study the underlying mechanism.METHODS Sprague Dawley(SD)rats were divided into some groups according to their serum uric acid(UA),the normal control group received standard diet,while others were fed with high-purine diet.After the success of modeling,SD rats were divided into 5groups according to UA:normal control group,model control group,Di.E and Gpm.E(high,middle,low dosages).The treatment groups were simultaneously orally administered.Two days before the last administration,the urine N-acetyl beta-D Glucosaminidase(NAG),Lysozyme(LYS)activity were separately detected using the urine collected from metabolic cage for 24 h.After the last administration,the blood was taken from postcava to detect the level:① The related indexes of liver and kidney function:the serum UA,blood urea nitrogen(BUN),creatinine(CR),alanine aminotransferase(ALT);② The uric acid metabolism related enzymes:the serum and liver xanthine oxidase(XOD),adenosine deaminase(ADA),guanine deaminase(GD),xanthine dehydrogenase(XDH)activity;③ Fibrosis related indexes of renal tissue:connective tissue growth factor(CTGF),monocyte chemotactic protein-1(MCP-1),TGF-β1,TNF-α,NF-κB levels.RESULTS Di.E and Gpm.E(high,middle dosages)could markedly reduce the serum UA level significantly,also can decrease XOD,ADA,TNF-α,MCP-1,NF-κB activity significantly.CONCLUSION The results show that Di.E and Gpm.E can decrease the serum UA level significantly,improve the liver and kidney function and slow down the process of renal fibrosis;the therapeutic effects may be related to their inhibition of XOD,ADA activity.     

黄嘌呤氧化酶抑制剂的研究进展

黄嘌呤氧化还原酶（Xanthine oxidoreductase,XOD)是一种高度通用的黄素酶,在不同物种之间以及生物各种组织中普遍存在。痛风是由于体内尿酸代谢障碍,导致尿酸水平过高,影响机体的正常运行。抑制黄嘌呤氧化还原酶可以降低尿酸水平,发挥抗高尿酸的作用。现如今临床上用于治疗痛风、高尿酸血症最有效的药物还是黄嘌呤氧化还原酶抑制剂。本文归纳了黄嘌呤氧化还原酶抑制剂的药理作用和临床应用,并对近年来已经上市和处于开发阶段的黄嘌呤氧化还原酶抑制剂进行总结,综述了黄嘌呤氧化还原酶抑制剂的最新进展。     

茶黄素对高尿酸血症小鼠的降尿酸作用研究

目的 研究茶黄素对高尿酸血症模型小鼠的降尿酸作用.方法 采用氧嗪酸钾诱导高尿酸血症小鼠模型,茶黄素低、中、高剂量(6、20、60 mg/kg)和别嘌呤(10 mg/kg)连续ig给药7 d,检测高尿酸血症小鼠血清尿酸(UA)、尿素氮(BUN)、肌酐(CRE)、天冬氨酸氨基转氨酶(AST)、丙氨酸氨基转氨酶(ALT)水平...     

降尿酸药物对高尿酸血症合并多系统并发症的影响研究进展

高尿酸血症是由体内尿酸生成过多或肾脏排泄障碍造成的尿酸在血液中积聚。长期高尿酸血症与肾功能损伤、代谢性疾病、心血管疾病等多种并发症的诱发风险及不良预后相关。降尿酸治疗是控制高尿酸血症及其并发症的必要手段,然而不同降尿酸药物对于不同并发症的预后有差异。本文对高尿酸血症相关并发症以及当前降尿酸药物对并发症的影响作一综述,以期为高尿酸血症患者在合并其他并发症时的降尿酸药物选择上提供安全有效的用药依据。     

土茯苓水提物对高尿酸血症模型小鼠血清尿酸和甘油三酯、胆固醇的影响

目的:研究土茯苓水提物对高尿酸血症模型小鼠血清尿酸(UA)和甘油三酯(TG)、胆固醇的影响。方法:实验分为空白(等容蒸馏水)、模型(等容蒸馏水)、土茯苓水提物(10g(生药)·kg-1)、别嘌呤醇(40mg·kg-1)组。ig酵母30g·kg-11周复制模型,复制模型成功后分别ig相应药物,7d后检测各组大鼠血中胆固醇、TG、UA含量和黄嘌呤氧化酶(XOD)活性。结果:与模型组比较,土茯苓组小鼠血清UA、TG、胆固醇含量和XOD显著降低(P>0.05或P<0.01)。结论:土茯苓对高尿酸血症模型小鼠肾功能有保护作用,对UA升高有明显的抑制作用。     

Reducing effect of mangiferin on serum uric acid levels in mice

Context: Mangiferin, a natural bioactive xanthone C-glycoside, is widely present in medicinal plants like the leaf of Mangifera indica L. (Anacardiaceae). It has been reported that mangiferin possesses a variety of biological activities, including antidiabetic, hepatoprotective, anti-inflammatory, antioxidant, and anticarcinogenic. Objective: The hypouricemic effect and xanthine oxidoreductase (XOR) inhibitory activity of mangiferin were investigated here for the first time. Materials and methods: The hypouricemic effect of mangiferin was investigated in normal and hyperuricemic mice induced by potassium oxonate. Mangiferin at a dose of 0.75-100.0 mg/kg was given intragastrically to mice. The serum urate levels were determined using the phosphotungstic acid method. The hepatic activities of xanthine dehydrogenase (XDH) and xanthine oxidase (XOD) in hyperuricemic mice were assayed using commercially available kits. Results: The results showed that mangiferin at a dose of 1.5, 3.0, and 6.0 mg/kg significantly reduced the serum urate levels (148.7 ± 37.8, 142.2 ± 44.5, 121.7 ± 21.7 μmmol/L) in hyperuricemic mice, compared with untreated hyperuricemic mice (201.8 ± 71.2 μmmol/L). However, mangiferin did not decrease the serum urate levels in normal mice until mangiferin was up to 100 mg/kg. In addition, the hepatic activities of XDH in hyperuricemic mice were significantly decreased by mangiferin, while no changes of XOD were observed. Acute toxicity study in mice showed that mangiferin was very safe at a dose of up to 25 g/kg. Discussion and conclusion: These findings demonstrate that mangiferin has the potential to be developed as a new therapeutic agent for the treatment of hyperuricemia and gout.     

姜黄降尿酸作用的实验研究

采用次黄嘌呤和氧嗪酸钾诱导的小鼠高尿酸模型,分别给予不同剂量姜黄醇提物,以小鼠血清尿酸(SUA),肝脏黄嘌呤氧化酶活性(XOD),尿液尿酸(UUA)排泄量等为指标。结果,姜黄高剂量醇提物具有显著的降低SUA、抑制XOD活性、促进UUA排泄量的作用。表明姜黄可通过抑制尿酸生成与促进尿酸排泄的双重途径而达到降低血清尿酸。     

Reducing effect of mangiferin on serum uric acid levels in mice

Context: Mangiferin, a natural bioactive xanthone C-glycoside, is widely present in medicinal plants like the leaf of Mangifera indica L. (Anacardiaceae). It has been reported that mangiferin possesses a variety of biological activities, including antidiabetic, hepatoprotective, anti-inflammatory, antioxidant, and anticarcinogenic.

Objective: The hypouricemic effect and xanthine oxidoreductase (XOR) inhibitory activity of mangiferin were investigated here for the first time.

Materials and methods: The hypouricemic effect of mangiferin was investigated in normal and hyperuricemic mice induced by potassium oxonate. Mangiferin at a dose of 0.75–100.0 mg/kg was given intragastrically to mice. The serum urate levels were determined using the phosphotungstic acid method. The hepatic activities of xanthine dehydrogenase (XDH) and xanthine oxidase (XOD) in hyperuricemic mice were assayed using commercially available kits.

Results: The results showed that mangiferin at a dose of 1.5, 3.0, and 6.0 mg/kg significantly reduced the serum urate levels (148.7 ± 37.8, 142.2 ± 44.5, 121.7 ± 21.7 µmmol/L) in hyperuricemic mice, compared with untreated hyperuricemic mice (201.8 ± 71.2 µmmol/L). However, mangiferin did not decrease the serum urate levels in normal mice until mangiferin was up to 100 mg/kg. In addition, the hepatic activities of XDH in hyperuricemic mice were significantly decreased by mangiferin, while no changes of XOD were observed. Acute toxicity study in mice showed that mangiferin was very safe at a dose of up to 25 g/kg.

Discussion and conclusion: These findings demonstrate that mangiferin has the potential to be developed as a new therapeutic agent for the treatment of hyperuricemia and gout.     

Rapidly separating dissolving microneedles with sustained-release colchicine and stabilized uricase for simplified long-term gout management

Despite growing prevalence and incidence, the management of gout remains suboptimal. The intermittent nature of the gout makes the long-term urate-lowering therapy (ULT) particularly important for gout management. However, patients are reluctant to take medication day after day to manage incurable occasional gout flares, and suffer from possible long-term toxicity. Therefore, a safe and easy-to-operate drug delivery system with simple preparation for the long-term management of gout is very necessary. Here, a chitosan-containing sustained-release microneedle system co-loaded with colchicine and uricase liposomes were fabricated to achieve this goal. This microneedle system was confirmed to successfully deliver the drug to the skin and maintain a one-week drug retention. Furthermore, its powerful therapeutic potency to manage gout was investigated in both acute gouty and chronic gouty models. Besides, the drug co-delivery system could help avoid long-term daily oral colchicine, a drug with a narrow therapeutic index. This system also avoids mass injection of uricase by improving its stability, enhancing the clinical application value of uricase. In general, this two-drug system reduces the dosage of uricase and colchicine and improves the patient's compliance, which has a strong clinical translation.