嘌呤核苷酸补偿对吗啡依赖大鼠嘌呤核苷酸分解代谢的影响

目的探讨外源性补偿嘌呤核苷酸对吗啡依赖大鼠嘌呤核苷酸分解代谢的影响。方法将60只♂Wistar大鼠随机分为对照组、吗啡组、吗啡+嘌呤核苷酸组、对照戒断组、吗啡戒断组和吗啡+嘌呤核苷酸戒断组,戒断组于d8给药后4h观察纳洛酮急性戒断症状。各组检测血尿酸(UA)、尿素氮(BUN)和肌酐(Cre)含量,以及血浆和大脑皮质腺苷脱氨酶(ADA)活性。结果吗啡+嘌呤核苷酸戒断组的戒断症状综合评分明显少于吗啡戒断组(P<0.01)。吗啡组及吗啡戒断组血UA含量均明显高于相应的对照组和相应的吗啡+嘌呤核苷酸组(P<0.05)。各组间BUN和Cre含量差异无显著性(P>0.05)。吗啡组及吗啡戒断组血浆及大脑皮质ADA活性明显高于相应的对照组和相应的吗啡+嘌呤核苷酸组(P<0.05或P<0.01)。结论补充嘌呤核苷酸可改善吗啡增强大鼠嘌呤核苷酸分解代谢作用。     

吗啡对大鼠嘌呤核苷酸分解代谢的促进作用及其可能的作用机制

目的　研究吗啡对嘌呤核苷酸分解代谢的影响及作用机制。方法　剂量递增腹腔注射吗啡 ,建立吗啡依赖大鼠模型。用试剂盒检测血浆尿酸含量、血浆及小肠组织黄嘌呤氧化酶 (XO)的活性。提取小肠组织总RNA ,采用逆转录聚合酶链反应检测小肠组织XOmRNA的水平 ,以β actinmR NA为内标。结果　动物血浆尿酸水平 ,3d和 7d吗啡用药组显示高于对照组 (P <0 0 5,n =10 ) ;3d、7d吗啡用药组动物血浆XO活性高于对照组 (P <0 0 5,n =10 ) ,在自然戒断 2组动物血浆XO活性也高于对照组 (P <0 0 1,n =10 ) ;3或 7d吗啡用药组动物小肠XO活性高于对照组 (P <0 0 5,n =10 ) ;7d吗啡用药组动物小肠XOmRNA表达水平高于对照组 (P <0 0 1,n =3 )。结论　吗啡促进嘌呤核苷酸分解代谢 ;其作用机制可能与吗啡提高大鼠小肠嘌呤核苷酸分解代谢关键酶XO的活性 ,增强其表达有关     

吗啡对嘌呤核苷酸分解代谢的影响—吗啡依赖的生化与分子生物学机制研究

目的 :研究吗啡依赖及戒断对嘌呤核苷酸分解代谢的影响与作用机制。方法 :建立吗啡依赖、戒断的大鼠模型 ,测定大鼠血浆中尿酸及腺苷脱氨酶 (ADA)含量 ;各组织中的腺苷脱氨酶含量以及大鼠脑顶叶、肝脏、小肠和肌肉组织中腺苷脱氨酶的基因转录产物。结果 :吗啡给药大鼠血浆尿酸水平明显升高 (P <0 0 5 ) ;吗啡给药及戒断期间 ,大鼠血浆ADA水平均显著升高 (P <0 0 5 ) ;吗啡给药组大鼠脑顶叶、肝脏、小肠和肌肉组织匀浆中的ADA含量都有不同程度的升高 (P <0 0 5 ) ,而在自然戒断期间 ,上述各组织ADA含量较给药组有所下降 ;吗啡给药 3d组大鼠脑顶叶、吗啡给药 7d组大鼠肝脏、小肠和肌肉组织中ADA的基因表达均明显升高 (P <0 0 5 ) ,除肌肉组织外 ,在自然戒断期间 ,上述各组织ADA的基因表达水平都有不同程度的恢复。结论 :嘌呤核苷酸分解代谢加强可能是吗啡的基本作用 ,也可能是依赖的重要原因之一。     

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。     

海洛因对大鼠黄嘌呤氧化酶和血尿酸的影响

目的:检测黄嘌呤氧化酶(xanthineoxidase ,XOD)和血浆尿酸含量,研究海洛因给药对嘌呤核苷酸分解代谢的影响。方法:建立海洛因给药、停药大鼠模型,测定尿酸及XOD含量。结果:给药组尿酸及XOD含量高于对照组。与给药组比较,两个停药组尿酸含量、血浆和肝XOD含量降低;停药8d组脑顶叶XOD含量降低,脑干XOD含量略有下降趋势。但两个停药组脑干XOD含量仍高于对照组。结论:海洛因通过增加XOD的含量,使嘌呤核苷酸分解代谢增强,且脑中这一作用消除较慢。     

The effect of allopurinol on the cerebral vasculature of patients with subcortical stroke; a randomized trial

AIMS

New preventative strategies for stroke are required. One promising strategy is uric acid reduction and xanthine oxidase inhibition with allopurinol. We sought to investigate whether allopurinol improves cerebrovascular reactivity (CVR) following subcortical stroke.

METHODS

We performed a randomized, double-blind, controlled study to investigate the effect of a 3-month course of 300 mg allopurinol once daily vs. placebo on CVR in individuals with recent (within 6 months) subcortical stroke. Participants were randomized on a 1 : 1 basis. CVR was defined as the percentage change in middle cerebral artery flow velocity following an intravenous injection of 15 mg kg⁻¹ of acetazolamide. Our primary end-point was the CVR difference between baseline and 3 months. Secondary end-points included measures of peripheral vascular reactivity and blood markers of inflammation and endothelial activation.

RESULTS

We enrolled 50 participants; 45 completed the protocol. Baseline serum urate was 0.35 mmol l⁻¹ (SD 0.1) and 0.34 mmol l⁻¹ (SD 0.1) in the allopurinol and placebo groups, respectively. There were no serious adverse events related to treatment. CVR did not change following treatment with allopurinol [median CVR change 0.89% after allopurinol (n= 20) and −0.68% after placebo (n= 25); 95% confidence interval for estimated difference in medians −13.4, 25.5, P= 0.64]. Urate was significantly lowered by allopurinol but no change in other secondary end-points was seen.

CONCLUSION

Xanthine oxidase inhibition with allopurinol has previously been shown to improve cerebrovascular function, but no benefit was seen in this study. It may therefore be that previous encouraging findings will not translate into important clinical benefits.     

拟黑多刺蚁乙醇提取物中降低小鼠血清尿酸水平活性部位的筛选与化学成分分析

目的研究拟黑多刺蚁乙醇提取物(EEPR)中降低高尿酸血症模型小鼠血清尿酸水平的活性部位及其主要化学成分。方法昆明小鼠分别ig给予别嘌醇0.04 g.kg-1(阳性对照),EEPR 0.128,0.256和0.512 g.kg-1,EEPR的石油醚部位0.079和0.158 g.kg-1,乙酸乙酯部位0.051和0.102 g.kg-1,正丁醇部位0.052和0.104 g.kg-1和水部位0.042和0.084 g.kg-1,每天1次,连续12 d。正常对照组和模型对照组ig给予等体积含0.3%吐温-80的水溶液。末次给药1 h后除正常对照组外,其余各组小鼠均ip给予次黄嘌呤0.6 g.kg-1。1 h后眼眶静脉丛取血,用磷钨酸比色法测定血清尿酸水平,酶比色法测定黄嘌呤氧化酶活性。对降低血清尿酸水平的活性部位进行GC-MS分析,鉴定其主要化学成分。结果高尿酸血症模型小鼠血清尿酸水平与正常对照组比较明显升高(P<0.01),别嘌醇0.04 g.kg-1,EEPR 0.256和0.512 g.kg-1可明显降低该模型小鼠血清尿酸水平(P<0.05),分别由模型组的(464±143)μmol.L-1下降到273±80,346±85和(302±72)μmo.l L-1(P<0.05)。EEPR中石油醚部位0.079和0.158 g.kg-1可显著降低该模型小鼠血清尿酸水平,分别由模型组的(446±139)μmo.lL-1下降到328±100和(314±112)μmol.L-1(P<0.05),其他部位各剂量组对血清尿酸水平均无明显影响。石油醚部位0.158 g.kg-1可明显抑制黄嘌呤氧化酶活性,由模型对照组的(18±8)U.L-1下降到(11±5)U.L-1(P<0.05)。GC-MS分析结果表明,石油醚部位的脂肪酸中,反式十八碳烯酸甲酯占60.77%,十六烷酸甲酯占18.99%,十六碳烯酸甲酯占9.31%。结论 EEPR中石油醚部位可降低高尿酸血症模型小鼠血清尿酸水平,不饱和脂肪酸为石油醚部位脂肪酸的主要成分。     

Nitric oxide, adenosine deaminase, xanthine oxidase and superoxide dismutase in patients with panic disorder: alterations by antidepressant treatment

OBJECTIVE: In the present study, we aimed to investigate whether nitric oxide (NO) levels and activities of xanthine oxidase (XO), superoxide dismutase (SOD), and adenosine deaminase (ADA) are associated with Panic disorder (PD) as well as impact of psychopharmacological treatments on NO, SOD, ADA, and XO levels in PD. METHOD: In this study, 32 patients and 20 healthy controls were included. The serum levels of NO, XO, SOD, and ADA were measured in the patients and controls. The patients were treated with antidepressant. RESULTS: ADA and XO levels of the patients were significantly higher than the controls. SOD levels of the patients were significantly lower than the controls but the difference was not statistically significant. Although NO levels of the patients were higher than the controls, the difference was not statistically significant. There was no correlation between PAS and the parameters studied (SOD, ADA, XO, and NO) of the patients. After 8 weeks of antidepressant treatment, ADA and SOD activities were increased whereas NO and XO levels decreased significantly. CONCLUSION: ADA, XO activity may have a pathophysiological role in PD, and prognosis of PD. Activity of these enzymes may be used to monitor effects of the antidepressant treatment.     

Therapeutic voyage of synthetic and natural xanthine oxidase inhibitors

Xanthine oxidase (XO) inhibitors are commonly used to treat gout, nephropathy, and renal stone diseases related to hyperuricemia. However, recent research has shown that these inhibitors may also have potential benefits in preventing vascular diseases, including those affecting the cerebrovasculature. This is due to emerging evidence suggesting that serum uric acid is involved in the growth of cardiovascular disease, and XO inhibition can reduce oxidative stress in the vasculature. There is a great interest in the development of new XO inhibitors for the treatment of hyperuricemia and gout. The present review discusses the many synthetic and natural XO inhibitors that have been developed which are found to have greater potency.     

Evaluating the urate-lowering effects of different microbial fermented extracts in hyperuricemic models accompanied with a safety study

Uric acid (UA) is an end product of purine metabolism by the enzyme xanthine oxidase (XOD). Hyperuricemia is characterized by the accumulation of serum UA and is an important risk factor for gout and many chronic disorders. XOD inhibitors or uricase (catalyzes UA to the more soluble end product) can prevent these chronic diseases. However, currently available hypouricemic agents induce severe side effects. Therefore, we developed new microbial fermented extracts (MFEs) with substantial XOD inhibition activity from Lactobacillus (MFE-21) and Acetobacter (MFE-25), and MFE-120 with high uricase activity from Aspergillus. The urate-lowering effects and safety of these MFEs were evaluated. Our results showed that MFE-25 exerts superior urate-lowering effects in the therapeutic model. In the preventive model, both MFE-120 and MFE-25 significantly reduced UA. The results of the safety study showed that no organ toxicity and no treatment-related adverse effects were observed in mice treated with high doses of MFEs. Taken together, the results showed the effectiveness of MFEs in reducing hyperuricemia without systemic toxicity in mice at high doses, suggesting that they are safe for use in the treatment and prevention of hyperuricemia.     

高尿酸血症的发病机制与药物治疗研究进展

高尿酸血症是由于嘌呤代谢紊乱使尿酸生成增多和（或）排泄减少所致的代谢性疾病。高尿酸血症不仅是引起痛风的重要生化基础,而且与高血压、高脂血症、动脉粥样硬化、肥胖、胰岛素抵抗的发生密切相关。因此,针对其发病机制和药物治疗的研究已成为关注热点。本文阐述了高尿酸血症的发病机制,并从抑制尿酸合成与促进尿酸排泄两个方面介绍了相关药物治疗的研究进展。     

红茴香小分子化合物降尿酸活性及ADMET性质的分子对接

目的明确红茴香降尿酸的活性成分及作用机制。方法通过检索相关文献建立红茴香已知小分子化合物配体库,从蛋白PDB数据库获得黄嘌呤氧化酶相关蛋白(1N5X,1FIQ)作为筛选降尿酸药物靶点,用Discovery Studio 3. 0(DS)中Lib Dock对接模块虚拟筛选黄嘌呤氧化酶抑制剂,用ADMET模块对药代动力学性质进行预测。结果红茴香中的黄酮苷类成分包括槲皮素-4'-O-β-D-葡萄糖苷、槲皮苷、芹菜素-6-O-β-D-芦丁糖苷等,与1N5X,1FIQ具有较高的对接分数和较为适合的ADMET性质。结论红茴香中黄酮苷类通过抑制黄嘌呤氧化酶活性具有降尿酸活性,可为进一步研究开发降尿酸药物提供参考。     

Effects of bikaverin on purine nucleotide synthesis and catabolism in Ehrlich ascites tumor cells in vitro

Bikaverin, a growth-inhibitory fungal metabolite, inhibits the incorporation of radioactive purine bases into nucleic acids and also into acid-soluble nucleotides. It also inhibits energy metabolism and induces the breakdown of intracellular ATP. Evidence is presented that these effects may be due to inhibition of ATP synthesis by bikaverin, probably at the level of the tricarboxylic acid cycle or oxidative phosphorylation.     

松叶提取物对“过食膏粱厚味”型高尿酸血症大鼠尿酸生成排泄、肝功能及血脂水平的影响

目的 研究松叶提取物对“过食膏粱厚味”型高尿酸血症大鼠尿酸生成排泄、肝功能及血脂水平的影响。方法 将60只♂SD大鼠,随机分为正常对照组、模型对照组、别嘌醇（0.01 g·kg^-1）阳性对照组、松叶提取物3个剂量组（10.0,5.0,2.5 g·kg^-1）,每组10只。除正常对照组给予等体积蒸馏水,其余各组每天上午灌胃给予脂肪乳剂造模,下午灌胃给药,连续9周。观察大鼠一般行为学、摄食量、体质量,分别检测大鼠血清SUA、SCR、BUN、ALT、AST、TC、LDL-c含量;收集24 h尿液,记录UV,检测大鼠尿UUA、UCR含量,计算24 h UUA、FEUA、CUr、CCr,末次给药后测定血清和肝脏XOD、ADA、HGPRT活性。结果 模型对照组大鼠体质量明显降低,血清SUA、SCR、BUN、ALT、TC、LDL-c水平以及血清和肝组织XOD、ADA活性显著升高,肝组织HGPRT活性显著降低,同时UUA、UCR、UV、24 h UUA、FEUA、CUr、CCr显著降低。松叶提取物能显著降低高尿酸血症大鼠血清SUA、SCR、BUN、ALT、TC、LDL-c水平,降低血清和肝组织XOD、ADA活性,升高肝组织HGPRT活性,并且升高UUA、UCR、UV、24 h UUA、FEUA、CUr、CCr。结论 松叶提取物能有效降低HUA大鼠尿酸的生成并促进其排泄,且具有保肝、调血脂的功能。     

Pharmacokinetics of pyrazinamide and its metabolites in healthy subjects

Summary The plasma and urine pharmacokinetic parameters of pyrazinamide and of its metabolites (pyrazinoic acid, 5-hydroxy-pyrazinamide, 5-hydroxy-pyrazinoic acid and pyrazinuric acid) have been studied after a single oral dose of pyrazinamide 27 mg · kg^–1 in 9 healthy subjects.Pyrazinamide was rapidly absorbed (t_max 1 h) and showed a short distribution phase followed by an elimination phase of t_1/2=9.6 h. The close similarity of the apparent elimination rates of the metabolites led to a second trial of a single oral dose of pyrazinoic acid to evaluate the formation and elimination stages.The limiting factor was found to be the activity of a microsomal deamidase (pyrazinoic acid formation from pyrazinamide and 5-hydroxy-pyrazinoic acid formation from 5-hydroxy-pyrazinamide). In contrast, oxidation by xanthine oxidase occurred very rapidly (5-hydroxy-pyrazinamide formation and pyrazinoic acid catabolism to 5-hydroxy-pyrazinoic acid).     

Pharmacological effects of Chatuphalatika in hyperuricemia of gout

Context: Chatuphalatika (CTPT), is a Thai herbal formulation mixture of Phyllanthus emblica Linn. (Euphorbiaceae), Terminalia belerica Linn. (Combretaceae), T. chebula and the fruit of T. arjuna (Roxb.) Wight &; Arn. CTPT is considered to exert anti-inflammatory and antihyperuricemic effects, but there have been no reports to demonstrate these pharmacological effects in a quantitative manner.

Objectives: To investigate the antioxidative, anti-inflammatory and antihyperuricemic effects of CTPT.

Materials and methods: Antioxidant activities of CTPT extracts were measured in vitro by DPPH, ABTS and FRAP assays, and anti-inflammatory effect by measuring inflammatory mediator production induced by lipopolysaccharide (LPS) in RAW264.7 macrophages. The mechanism of the hypouricemic effect was investigated using oxonate-induced hyperuricemic ddY mice treated with oral administrations of CTPT at 250, 500 and 1000?mg/kg.

Results: Antioxidant activities of CTPT measured by ABTS and FRAP assays were 1.35?g TEAC/g extract and 10.3?mmol/100?g extract, respectively. IC₅₀ for the inhibition of DPPH radical was 13.8?µg/mL. CTPT (10?µg/mL) significantly downregulated the mRNA expression of TNF-α and iNOS in RAW 264.7 cells. Lineweaver–Burk analysis of the enzyme kinetics showed that CTPT inhibited xanthine oxidase (XOD) activity in a noncompetitive manner with the K_i of 576.9?µg/mL. Oral administration of CTPT (1000?mg/kg) significantly suppressed uric acid production by inhibiting hepatic XOD activity, and decreased plasma uric acid levels in hyperuricemic mice by approximately 40% (p?Conclusions: This study demonstrated for the first time the antioxidative, anti-inflammatory and antihyperuricemic effects of CTPT in vivo and in vitro, suggesting a possibility of using CTPT for the treatment of hyperuricemia in gout.     

Mechanism-based pharmacokinetic–pharmacodynamic modeling of salvianolic acid A effects on plasma xanthine oxidase activity and uric acid levels in acute myocardial infarction rats

1.?Salvianolic acid A (SalA) was found to attenuate plasma uric acid (UA) concentration and xanthine oxidase (XO) activity in acute myocardial infraction (AMI) rats, which was characterized with developed mechanism-based pharmacokinetic–pharmacodynamic (PK-PD) model.

2.?AMI was induced in rats by coronary artery ligation. Surviving AMI rats received a single intravenous dose of 5?mg/kg of SalA and normal saline. The plasma SalA concentrations were determined by HPLC-MS/MS method. The plasma UA concentrations were determined by HPLC method and plasma XO activity were measured spectrophotometrically. An integrated mathematical model characterized the relationship between plasma UA and SalA.

3.?Pharmacokinetics was described using two-compartment model for SalA with linear metabolic process. In post-AMI rats, XO activity and UA concentrations were increased, while SalA dosing palliated this increase. These effects were well captured by using two series of transduction models, simulating the delay of inhibition on XO driven by SalA and UA elevation resulted from the multiple factors, respectively.

4.?The effect was well described by the developed PK-PD model, indicating that SalA can exert cardiovascular protective effects by decreasing elevated plasma UA levels induced by AMI.     

Design,synthesis, and evaluation of the in vitro activity of novel dual inhibitors of XOR and URAT1 containing a benzoic acid group

Xanthine oxidoreductase (XOR) and uric acid transporter 1 (URAT1) are involved in the production and reabsorption of uric acid, respectively. However, the currently available individual XOR- or URAT1-targeted drugs have limited efficacy. Thus, strategies for combining XOR inhibitors with uricosuric drugs have been developed. Previous virtual screening identified Compounds 1 – 5 as hits for the potential dual inhibition of XOR/URAT1. Nevertheless, in vitro experiments yielded unsatisfactory results. The first round of optimization work on those hits was performed, and two series of compounds were designed and synthesized. Compounds of the A series exerted moderate inhibitory effects on URAT1, but extremely weak inhibitory effects on XOR. Compounds of the B series exerted strong inhibitory effects on both XOR and URAT1. B ₅ exhibited the greatest inhibitory activity, with similar inhibitory effects on XOR and URAT1. The half maximal inhibitory concentration (IC₅₀) of XOR was 0.012 ± 0.001 μM, equivalent to that of febuxostat (IC₅₀ = 0.010 ± 0.001 μM). The IC₅₀ of URAT1 was 30.24 ± 3.46 μM, equivalent to that of benzbromarone (IC₅₀ = 24.89 ± 7.53 μM). Through this optimization, the in vitro activity of most compounds of the A and B series against XOR and URAT1 was significantly improved versus that of the hits. Compound B ₅ should be further investigated.     

Natural compounds with xanthine oxidase inhibitory activity: A review

Hyperuricemia (HUA), a disease due to an elevation of body uric acid level and responsible for various diseases such as gout, cardiovascular disorders, and renal failure, is a major ground debate for the medical science these days. Considering the risk factors linked with allopathic drugs for the treatment of this disease, the debate has now become a special issue. Previously, we critically discussed the role of dietary polyphenols in the treatment of HUA. Besides dietary food plants, many researchers figure out the tremendous effects of medicinal plants‐derived phytochemicals against HUA. Keeping in mind all these aspects, we reviewed all possible managerial studies related to HUA through medicinal plants (isolated compounds). In the current review article, we comprehensively discussed various bioactive compounds, chemical structures, and structure–activity relationship with responsible key enzyme xanthine oxidase.