酵母膏联合氧嗪酸钾构建高尿酸血症模型大鼠继发的心血管病变☆

背景：高尿酸血症动物模型的构建是研究高尿酸血症与肾脏和心血管疾病相互关系的重要手段。 目的：采用酵母膏和不同剂量的氧嗪酸钾建立高尿酸血症动物模型,寻找建模的最佳剂量。 方法：以酵母膏(21 g/kg)或酵母膏联合不同剂量氧嗪酸钾(50~200 mg/kg)持续灌胃或腹腔注射28 d建立高尿酸血症大鼠模型。 结果与结论：酵母膏或酵母膏联合50~200 mg/kg氧嗪酸钾持续灌胃或酵母膏联合50~100 mg/kg氧嗪酸钾腹腔注射均能显著提高大鼠血清高尿酸水平,而对大鼠肾、心和动脉功能无明显影响。酵母膏联合200 mg/kg氧嗪酸钾腹腔注射不仅使大鼠血清尿酸维持在高水平,也可引起大鼠肾脏、心脏及动脉形态和病理改变。说明酵母膏联合200 mg/kg氧嗪酸钾腹腔注射是建立持续、稳定高尿酸血症动物模型的最佳配伍剂量,也是研究高尿酸血症引起继发性心血管病理损伤的良好模型。 关键词：尿酸;高尿酸血症;模型;氧嗪酸钾;酵母膏;心血管病变 doi:10.3969/j.issn.1673-8225.2012.11.022     

尿酸转运蛋白是治疗高尿酸血症的新靶点

肾小管上皮细胞存在多种尿酸转运相关蛋白,按照功能不同可分为重吸收相关蛋白、排泄相关蛋白和骨架蛋白.尿酸盐转运子1、葡萄糖转运子9和ATP结合盒蛋白家族G蛋白亚家族成员2是最重要的尿酸转运蛋白;PDZK1为其他蛋白提供结构支持.这些尿酸转运蛋白是高尿酸血症和其他代谢紊乱的纽带,也是新型降尿酸药物的研究靶点.     

氯沙坦钾下调尿酸性肾纤维化大鼠肾小管上皮细胞尿酸转运蛋白-1的表达

目的研究氯沙坦钾对高尿酸血症致尿酸性肾纤维化大鼠肾小管上皮细胞尿酸转运蛋白-1(URAT1)表达的影响。方法将大鼠随机分为正常组、模型组(以腺嘌呤100 mg/kg+乙胺丁醇250 mg/kg的混悬液灌胃造模)、氯沙坦钾低、中和高剂量灌胃治疗组[分别为25、50和75 mg/(kg·d)]。各组于造模后第1、2、3和4周检测大鼠血尿酸、血肌酐、尿素氮、尿酸、尿肌酐和尿酸排泄分数,用HE和Masson染色法观察尿酸性肾纤维化大鼠病理变化,Western blot检测肾小管上皮细胞URAT-1蛋白的表达。结果随着时间的延长,模型组大鼠血尿酸水平显著高于正常组(P0.01),尿尿酸水平低于正常组(P0.01);各治疗组血尿酸水平下降,尿尿酸水平升高,以高剂量组为著(P0.05);模型组肾小管间质损伤指数明显高于同期正常组(P0.05),氯沙坦钾干预后肾小管间质损伤指数明显降低(P0.05); URAT1蛋白表达在模型组各时间段升高(P0.05),且随着病理损害的进展呈现上升趋势,经氯沙坦钾干预后表达明显下降(P0.05)。结论氯沙坦钾可下调URAT1高表达,降低高尿酸血症大鼠的血尿酸水平。     

健康体检人群血清尿酸水平及高尿酸血症的分布特点分析

目的研究健康体检人群血清尿酸(SUA)水平及高尿酸血症(HUA)的分布特点。方法选取2018年2月至2019年2月我院健康体检人群20874例并采集晨起空腹外周静脉血5 mL,凝固、分离后取上清,采用酶比色法检测SUA水平同时进行HUA诊断,分析不同年龄和性别人群SUA水平和HUA检出率变化,比较不同SUA水平人群高血压、糖尿病及心血管疾病等发生率。结果60岁以上男性SUA水平低于18~60岁组;50岁以上女性SUA水平高于18~50岁组,60岁以上女性SUA水平高于51~60岁组;且各年龄段男性SUA水平均高于女性,差异有统计学意义(P<0.05);20874例受检者中共检出HUA患者4584例,占比21.96%,男性和女性HUA检出率分别为29.39%和13.80%,其中男性60岁以上年龄段HUA检出率明显低于18~60岁组,女性HUA检出率随年龄增加而升高,51~60岁年龄段HUA检出率高于18~50岁组,60岁以上年龄段HUA检出率高于18~60岁组,且18~60岁年龄段男性HUA检出率高于女性,60岁以上年龄段男性HUA检出率低于女性,差异均有统计学意义(P<0.05);多因素Logistic回归分析显示,男性、HUA家族史、BMI增加、GFR降低、饮酒史、糖尿病以及高脂血症均为HUA发病的独立危险因素(P<0.05)。结论60岁以上男性SUA水平明显降低,50岁以上女性SUA水平明显升高,针对不同年龄段男性和女性分别制定相应参考值范围有利于提升HUA诊断和治疗水平,对改善患者身心健康具有重要意义。     

尿酸对树突状细胞成熟及免疫功能的影响

 目的：观察尿酸（UA）对体外培养的小鼠骨髓来源树突状细胞（BMDCs）成熟及免疫功能的影响。方法：体外分离培养小鼠骨髓来源的DC，使用GM-CSF、IL-4、LPS，并加入UA诱导培养DC。用流式细胞仪技术检测BMDCs细胞表面分子表达，用MTT法检测BMDCs与同基因小鼠T淋巴细胞的混合淋巴细胞反应；ELISA法测定DC培养上清IL-12的水平。结果：通过鉴定体外成功诱导培养出BMDCs。尿酸浓度为400mg/L或200 mg/L时能增强DC细胞表面CD11c、CD83、CD86、IA/IE分子表达率；提高IL-12分泌水平（P＜0.05）； DC与T淋巴细胞比例分别为5∶1、10∶1、20∶1时，能增强DC刺激T细胞增殖能力（P＜0.05）；尿酸浓度为70 mg/L时，细胞表面分子表达、IL-12分泌水平、刺激T细胞增殖作用与对照组比较均无明显差别（P＞0.05）。结论：对体外培养诱导扩增的BMDCs， UA可促进分化与成熟，提高表面共刺激分子表达；增强其刺激T细胞增殖能力和IL-12分泌水平。UA的作用与浓度密切相关。     

谷胱甘肽对酵母多糖诱导的小鼠肝TNF-α基因表达的影响

在分子水平上研究谷胱甘肽对酵母多糖诱导的小鼠肝组织肿瘤坏死因子－α基因表达的影响。腹腔注射（ip)谷胱甘肽（20mg/kg)，然后ip酵母多糖（0.5g/kg)。RT－PCR检测肝组织TNF－αmRNA水平，放射免疫地检测TNF－α蛋白水平及DTNB显色法检测谷胱甘肽过氧化物酶（GSH－Px)活性。发现损伤组肝组织TNF－αmRNA，蛋白水平高于对照组（P＜0．05），谷胱甘肽组肝组织TNF－αmRNA，蛋白水平都低于损伤组。谷胱甘肽组肝组织谷胱甘须过氧化物酶活性高于其他各组（P＜0．05）。谷胱甘肽抑制了由酵母多糖诱导的小鼠肝组织TNF－αmRNA蛋白的表达。     

尿酸与癌症的关系

癌症(Cancer)是威胁人类健康的第一杀手,其发生机制包括机体处于氧化应激态,DNA、蛋白质等结构和功能受损,最终诱发细胞凋亡和基因组损伤而发病。尿酸作为人体天然抗氧化剂,能清除体内氧化物,保护生物大分子,抑制癌症的发生发展,可能为未来抗癌治疗提供新的方向。     

多发性硬化患者血清尿酸水平测定的临床意义

目的探讨多发性硬化患者血清尿酸的水平及其临床意义。方法采用放射免疫法对24例多发性硬化患者治疗前后进行了血清尿酸测定。结果多发性硬化患者血清尿酸水平均显著降低,与对照组比较有显著性差异,治疗后进入稳定期尿酸水平有所提高,与对照组比较无显著性差异。结论测定多发性硬化患者血清尿酸水平有助于了解病情,判断病情活动性,尿酸对多发性硬化有保护作用,值得进一步研究。     

原发性高尿酸血症发病机制的研究进展

高尿酸血症和痛风的患病率逐年升高,而且与代谢综合症密切相关,因此对高尿酸血症发病机制的研究日益增多。高尿酸血症是由于尿酸合成增加及/或尿酸排泄减少所引起。长期的高尿酸血症易诱发痛风,还可伴发高血压、肥胖、糖尿病、肾脏疾病及心脑血管疾病等。近年来,尿酸合成增加的机制已基本明确,而导致尿酸排泄减少的分子机制尚不清楚。本文从尿酸合成增加和排泄减少两方面对原发性高尿酸血症的发病机制研究进展进行综述。     

尿酸在心肾代谢综合征的作用

血清尿酸水平已被证实与肥胖,高血压,心血管疾病和肾脏疾病,以及心肾代谢综合征(CRS)密切相关。升高的血清尿酸水平可引起血管内皮功能障碍,血管硬化,肾素-血管紧张素-醛固酮系统的异常激活,增强氧化应激和非特异性免疫和炎症反应。这些异常,进而促进血管,心脏和肾脏的纤维化以及相关的功能异常。小规模的临床试验表明,降尿酸疗法可以有利于患者,然而,对无症状的高尿酸血症的治疗仍缺乏共识。     

Acute uric acid nephropathy in two gouty patients with moderate hyperuricemia and high urine acidity

Summary Acute uric acid nephropathy has been described almost uniformly in patients with massive uric acid overload (malignancies with rapid cell destruction, epileptic seizures). Severe hyperuricosuria and intratubular uric acid precipitation result. Here we present two patients with gout, normal uric acid production, and moderate hyperuricemia, both of whom developed acute uric acid nephropathy. Because of pronounced urine acidity (pH values of 4.6 and 5.0 in morning fasting urines), supersaturation with respect to undissociated uric acid exceeded solubility (0.54 mmol/l), despite basal urate secretions of less than 2.2 mmol/24 hours. Additional predisposing factors, such as uricosuric treatment, heavy beer-drinking, over-consumption of purine-rich foods, and hot environment, were superimposed in both cases.Abbreviations S_Cr serum creatinine - S_UA serum uric acid - GFR glomerular filtration rate - C_Cr creatinine clearance - C_Urate urate clearance - UV_Urate urinary excretion of urate - UUA urinary undissociated uric acid - TUA urinary total uric acid - FE_Urate fractional excretion of urate     

Acute lobular (membranoproliferative) glomerulonephritis with hyperuricemia and obstructive uric acid nephropathy.

Obstructive uric acid nephropathy, a potentially lethal complication of acute renal failure due to glomerulonephritis, is described and illustrated. The factors leading to its occurrence and the reasons it may be undetected are detailed. Lobular glomerulonephritis is also briefly defined once again.     

Melphalan in ultralow doses decreases the severity of experimental colitis in mice

We studied the effect of melphalan in ultralow doses on mice with experimental colitis induced by substitution of drinking water for 5% dextran sulfate. Daily treatment with melphalan in a dose of 0.025 mg/kg improved the general state of animals. The influence of melphalan was evaluated by quantitative clinical, pathomorphological, and laboratory parameters. Melphalan had a local and systemic antiinflammatory effect. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 142, No. 10, pp. 418–422, October, 2006     

The influence of uric acid treatments on liver glutathione system prevent oxidative damages in experimental autoimmune encephalomyelitis mice

Recently we reported that antioxidant system in brain and spinal cord in experimental autoimmune encephalomyelitis (EAE) mice is mainly affected at early stages of the disease [M. Zargari, A. Allameh, M.H. Sanati, T. Tiraihi, S.H. Lavasani, O. Emadyan, Relationship between the clinical scoring and demyelination in central nervous system with total antioxidant capacity of plasma during experimental autoimmune encephalomyelitis development in mice, Neurosci. Lett. 412 (2007), 24–28]. The aim of the present study was to investigate the role of uric acid (UA) on antioxidant system in liver and plasma of EAE mice. EAE was induced in C57/BL6 mice (n = 60), followed by i.p. administration of UA (10 mg/kg BW) in 30 mice at three distinct clinical stages (A: prior to onset, B: after onset, C: after development of EAE). Livers were removed and processed for measurement of lipid peroxidation products, reduced glutathione (GSH), and glutathione S-transferase (GST) and total antioxidant capacity of plasma (FRAP). The results showed that lipid peroxidation products in liver of EAE mice was increased significantly (∼85%) as compared to normal. UA administration to EAE mice caused a significant suppression of liver lipid peroxidation products (∼45%) at early stages (A and B). There was an inverse relationship between lipid peroxidation and cellular GSH in liver. GSH was significantly depleted in mice liver during the EAE progression, but it was recovered (∼29%) when UA was injected before the onset of the disease (groups A and B). Plasma total antioxidant capacity was significantly decreased during the development of EAE, however it was subsided in mice treated with UA as compared to the corresponding controls (21%) in groups A and B. Elevated liver GST as a result of EAE induction was reversed in mice treated with UA particularly in groups A and B. These results indicate that hepatic glutathione system, particularly GST plays a major role in modulation of oxidative damages to central nervous system (CNS) during EAE induction. The positive response of antioxidant system to UA administration in EAE mice was corroborated with improvement of clinical manifestation of the animals.     

氯沙坦改善慢性充血性心力衰竭病人心功能并降低血尿酸

目的观察血管紧张素Ⅱ受体拮抗剂氯沙坦对充血性心力衰竭的心功能的改善作用及其对血尿酸的影响。方法85例充血性心力衰竭患者在应用强心、利尿、扩血管及β受体阻滞剂治疗的基础上随机分为:氯沙坦组(43例),苯那普利对照组(42例)。治疗前后分别进行心功能评估,血尿酸、心电图、超声心动图等检查。结果治疗前两组间心功能、心率、左室舒张末内径,左室射血分数、心胸比无显著性差异。经治疗3个月、12月后,两组心功能、心率、左室舒张末内径,左室射血分数、心胸比较治疗前均有明显改善(P<0·01)。治疗后两组血尿酸均有不同程度的下降,氯沙坦组治疗后血尿酸较治疗前显著降低36·5%(P<0·01),比苯那普利组下降更显著(P<0·05)。结论氯沙坦既可改善充血性心力衰竭患者的临床症状及心功能,减缓心力衰竭的病程发展,又可作为充血性心力衰竭合并血尿酸增高患者降低血尿酸的有效药物。     

Aluminum enhances inflammation and decreases mucosal healing in experimental colitis in mice

The increasing incidence of inflammatory bowel diseases (IBDs) in developing countries has highlighted the critical role of environmental pollutants as causative factors in their pathophysiology. Despite its ubiquity and immune toxicity, the impact of aluminum in the gut is not known. This study aimed to evaluate the effects of environmentally relevant intoxication with aluminum in murine models of colitis and to explore the underlying mechanisms. Oral administration of aluminum worsened intestinal inflammation in mice with 2,4,6-trinitrobenzene sulfonic acid- and dextran sodium sulfate-induced colitis and chronic colitis in interleukin 10-negative (IL10^−/−) mice. Aluminum increased the intensity and duration of macroscopic and histologic inflammation, colonic myeloperoxidase activity, inflammatory cytokines expression, and decreased the epithelial cell renewal compared with control animals. Under basal conditions, aluminum impaired intestinal barrier function. In vitro, aluminum induced granuloma formation and synergized with lipopolysaccharide to stimulate inflammatory cytokines expression by epithelial cells. Deleterious effects of aluminum on intestinal inflammation and mucosal repair strongly suggest that aluminum might be an environmental IBD risk factor.     

Mefenamic acid decreases inflammation but not joint lesions in experimental osteoarthritis

Mefenamic acid is a non‐steroidal anti‐inflammatory drug able to control the symptoms of osteoarthritis (OA), but its effects on protection of cartilage and bone are still unclear. This study aimed to investigate whether the control of inflammation by mefenamic acid translates into decreased joint lesions in experimental OA in rats. OA was induced by injecting 1 mg of monosodium iodoacetate (MIA) into the joints of rats. The animals were treated with mefenamic acid (50 mg/kg, daily, oral gavage) either pre‐MIA injection (preventive) or post‐MIA injection (therapeutic). Joint swelling and hyperalgesia were evaluated at baseline and 1, 3, 14 and 28 days after induction of OA. Intra‐articular lavage and kinetics of cell migration into the synovium were measured 3 and 28 days after OA induction. Histopathological analysis, Osteoarthritis Research Society International (OARSI) score, total synovium cells count, cartilage area and levels of proteoglycans in joints were also evaluated. Mefenamic acid prevented joint oedema and hyperalgesia induced by MIA in the acute phase (3 days) of the disease. In the chronic phase (28 days), preventive and therapeutic regimens decreased the number of mononuclear cells in the joint cavity. In contrast, thickening of the synovium, bone resorption, loss of cartilage and levels of proteoglycans were unaffected by mefenamic acid when it was administered either preventively or therapeutically. Thus, mefenamic acid had anti‐inflammatory effects but did not reduce the progression of OA lesions, thereby indicating that it is only effective for symptomatic control of OA.     

Extracorporeal uric clearance for the demonstration of in vivo bound uric acid

Although numerous in vitro experiments demonstrated a variable degree of urate bound to human serum albumin and other macromolecules of human plasma, only few data are available on in vivo bound urate. Extracorporal clearances of uric acid, urea nitrogen, creatinine and phosphorus were performed at the beginning, the midtime and the end of 10 hours of hemodialysis. A continuous decrease of uric acid clearance was observed in ratio with the capacity of the artificial kidney used. In contrast to uric acid the clearances of urea nitrogen, creatinine and phosphorus remained constant during the time of dialysis. From the fall of uric acid clearance, the authors conclude a partial binding of uric acid in human plasma.