氨基胍在实验大鼠肺纤维化中的作用及机制初探

目的 初步探讨氨基胍(aminoguanidine,AG)在博莱霉素(bleomycin,BLM)诱导的大鼠肺纤维化模型中的作用及其机制.方法 实验第1天将48只SD大鼠随机分为8组:正常对照组、BLM模型组、AG干预组及AG对照组(包括低、中、高3个剂量组),每组6只,经气道滴入BLM/生理盐水后,于实验第2天开始按低、中、高3个剂量给予AG,2周后处死所有大鼠,收集标本.利用Masson染色,观察肺组织纤维化的情况,并进行纤维化评分;利用碱性水解法测定肺组织中羟脯氨酸的含量;利用RT-PCR的方法测定肺组织中热休克蛋白47的基因表达.结果 AG干预组与BLM模型组相比较,前者的纤维化程度均有所减轻,且呈现出剂量依赖性,尤其在中、高剂量组,纤维化评分、羟脯氨酸含量、热休克蛋白47的基因表达出现明显下降(P值均＜0.01).AG对照组与正常对照组比较差异无统计学意义.结论 AG能有效降低BLM诱导的肺纤维化程度,其机制可能与下调热休克蛋白47等纤维化因子的表达有关.     

Protective effect of inducible nitric oxide synthase inhibitor on pancreas transplantation in rats

AIM： To investigate the effect of inducible nitric oxide synthase inhibitor, aminoguanidine, on pancreas transplantation in rats. METHODS： A model of pancreas transplantation was established in rats. Streptozotocin-induced diabetic male Wistar rats were randomly assigned to sham-operation control group （n = 6）, transplant control group （n = 6）, and aminoguanidine （AG） treatment group （n = 18）. In the AG group, aminoguanidine was added to intravascular infusion as the onset of reperfusion at the dose of 60 mg/kg, 80 mg/kg, 100 mg/kg body weight, respectively. Serum nitric oxide （NO） level, blood sugar and amylase activity were detected. Nitric oxide synthase （NOS） test kit was used to detect the pancreas cNOS and inducible NOS （iNOS） activity. Pancreas sections stained with HE and immunohistochemistry were evaluated under a light microscope. RESULTS： As compared with the transplant control group, the serum NO level and amylase activity decreased obviously and the evidence for pancreas injury was much less in the AG group. The AG （80 mg/kg body weight） group showed the most significant difference in NO and amylase （NO： 66.0 ± 16.6 vs 192.3 ± 60.0, P 〈 0.01 and amylase： 1426 ± 177 vs 4477± 630, P 〈 0.01）. The expression and activity of tissue iNOS, and blood sugar in the AG （80 mg/kg body weight） group were much lower than those in the transplant control group （iNOS： 2.01 ± 0.23 vs 26.59 ±5.78, P 〈 0.01 and blood sugar： 14.2 ±0.9 vs 16.8 ± 1.1, P 〈 0.01）. CONCLUSION： Selective iNOS inhibitor, aminoguanidine as a free radical, has a protective effect on pancreas transplantation in rats by inhibiting NO and reducing its toxicity.     

Glycation amplifies lipoprotein(a)-induced alterations in the generation of fibrinolytic regulators from human vascular endothelial cells

Increased lipoprotein(a) [Lp(a)] in plasma is an independent risk factor for premature cardiovascular diseases. The levels of glycated Lp(a) are elevated in diabetic patients. The present study demonstrated that glycation enhanced Lp(a)-induced production of plasminogen activator inhibitor-1 (PAI-1), and further decreased the generation of tissue-type plasminogen activator (t-PA) from human umbilical vein endothelial cells (HUVEC) and human coronary artery EC. The levels of PAI-1 mRNA and its antigen in the media of HUVEC were significantly increased following treatments with 5 μg/ml of glycated Lp(a) compared to equal amounts of native Lp(a). The secretion and de novo synthesis of t-PA, but not its mRNA level, in EC were reduced by glycated Lp(a) compared to native Lp(a). Treatment with aminoguanidine, an inhibitor for the formation of advanced glycation end products (AGEs), during glycation normalized the generation of PAI-1 and t-PA induced by glycated Lp(a). Butylated hydroxytoluene, a potent antioxidant, inhibited native and glycated Lp(a)-induced changes in PAI-1 and t-PA generation in EC. The results indicate that glycation amplifies Lp(a)-induced changes in the generation of PAI-1 and t-PA from venous and arterial EC. This may attenuate fibrinolytic activity in blood circulation and potentially contributes to the increased incidence of cardiovascular complications in diabetic patients with hyperlipoprotein(a). EC-mediated oxidative modification and the formation of AGEs may be implicated in glycated Lp(a)-induced alterations in the generation of fibrinolytic regulators from vascular EC.     

氨基胍对梗阻性黄疸大鼠治疗作用的实验研究

目的 探讨诱导型一氧化氮合酶(iNOS)抑制剂氨基胍(AG)对梗阻性黄疸大鼠的治疗作用及作用机制.方法 雄性Wistar大鼠40只,随机分为正常对照组、假手术组、黄疸组、氨基胍治疗组4组,每组10只.通过测定治疗前后肝功、血胆红素、内毒素、乳酸、肝组织丙二醛水平,以及通过对肝脏、小肠的形态学分析来探讨氨基胍对梗阻性黄疽大鼠的治疗作用.结果 血浆内毒素和血清乳酸、肝组织丙二醛随着胆道梗阻时间的延长逐步升高,并伴随着肝脏小肠病理形态学的改变.氨基胍治疗组各项指标显著低于对照组,并能改善肝组织及小肠病理形态.结论 氨基胍(AG)可通过减轻脂质过氧化与内毒素血症发挥保护肝脏及小肠的作用,为治疗梗阻性黄疸患者提供了一种新的思路和方法.

Abstract：

Objective To evaluate the therapeutic effect and mechanism of specific inducible nitric oxide synthase(iNOS)aminoguanidine(AG)in rats with obstructive jaundice.Methods Forty male Wistar rats were divided randomly into four groups: normal control group, sham operation group, obstructive jaundice group and aminoguanidine therapeutic group.Each group had 10 rats.We assayed levels of liver function,hemobilirubin, endotoxin,lactic acid and malondialdehyde before and after therapy, and we also analyzed pathology of the liver and small intestine.Then we could explore the therapeutic effect of AG in rats with obstructive jaundice.Results The levels of endotoxin,lactic acid and malondialdehyde in blood increased progressively along with the pathological changes of the liver and small intestine.Each of the AG group parameters was significantly lower, and the pathological changes of liver and small intestine were improved.Conclusion AG could protect liver and small intestine by attenuating lipid peroxidative and endotoxemia,and provide a new way to cure obstructive jaundice.     

补肾方剂对糖尿病大鼠牙周炎的疗效观察

目的观察补肾方剂对糖尿病大鼠牙周炎的治疗效果。方法选择60只大鼠建立糖尿病牙周炎模型,按照给药的不同分为单纯牙周炎组(不给药)、灌喂中药组(补肾方剂)、灌喂氨基胍(AG)组;同时选择16只正常大鼠作为对照组,给药4周、6周后均制作组织切片,观察牙周组织形态结构的变化,测定牙龈中一氧化氮(NO)含量。结果灌喂中药组的结缔组织附着丧失量、牙槽骨高度丧失量、牙龈组织中NO的含量均明显低于其他糖尿病牙周炎组,差异有统计学意义(P<0.05)。结论补肾方剂对促进糖尿病牙周炎牙周组织的修复,降低NO含量的作用优于AG。     

氨基胍对大鼠创伤性面瘫恢复及面神经核IL-6表达的影响

 目的研究诱导型一氧化氮合酶抑制剂氨基胍对大鼠创伤性面瘫恢复的影响及面神经核内IL-6表达的变化.方法通过大鼠面瘫前后腹膜内小剂量给予氨基胍,在伤后各个时间点上观察面瘫的恢复情况,并采用免疫组织化学ABC法对面神经核内IL-6阳性神经元的变化进行研究.结果氨基胍在创伤性面瘫的轻、中度恢复上有促进作用,其面神经核内IL-6免疫反应性明显比对照组增强.结论氨基胍慢性干预明显促进面神经核内IL-6的表达,并促进创伤性面瘫的轻、中度恢复.     

维生素E和氨基胍在糖尿病肾病治疗中的协同作用

目的探讨维生素E和氨基胍在糖尿病肾病（DN）治疗中的协同作用。方法①以一次性腹腔注射链脲佐菌素（STZ，55mg／kg）诱导糖尿病大鼠模型，将大鼠分为正常对照组、糖尿病对照组、糖尿病加维生素E治疗组、糖尿病加氨基胍治疗组、糖尿病加维生素E加氨基胍治疗组；②观察1、2、4、8、12、16周时各组大鼠24h尿白蛋白排泄率（UAER），16周时各组大鼠尿素氮（BUN）、血肌酐（SCr）及肾组织病理改变情况；③观察各组大鼠16周时肾小球活性氧（ROS）聚集情况以及肾间质8-羟基脱氧鸟苷（8-OHDG）表达情况。结果与糖尿病组比较，维生素E治疗组在2周时UAER明显下降，但在4、8、12、16周时两组比较无统计学意义；氨基胍治疗组和两药合用组则在包括2周以后的各时间点UAER均较糖尿病组明显下降，且两药合用组UAER下降更明显。16周时各组间BUN、SCr差异无统计学意义。16周时糖尿病组大鼠肾小球系膜区增宽，系膜基质聚集；维生素E治疗组肾组织病理无改善，氨基胍治疗组略有改善，而两药合用组则有明显改善。16周时糖尿病组大鼠肾小球ROS聚集，肾间质8-OHDG表达增强，维生素E组肾组织ROS聚集和8-OHDG表达未减轻，氨基胍治疗有一定程度减轻，两药合用组肾组织ROS聚集和8-OHDG表达则明显减轻。结论维生素E和氨基胍在DN的治疗中具有协同作用，而这一协同作用可能通过协同抗氧化来实现。     

氨基胍对炎症性痛大鼠痛阈的影响

目的:氨基胍对炎症性痛大鼠痛阈的影响.方法:用热板法观测鞘内注射诱导型NOS抑制剂氨基胍(AG)对大鼠右后掌皮下注射甲醛诱发的炎症性痛及痛过敏过程中不同时段痛阈的影响.结果:抑制剂对皮下注射甲醛后第一期痛阈(5分钟内)并无显著变化,而第二期(10-75分钟)痛阈均明显升高.结论:在大鼠后掌注射甲醛所引起的痛及痛过敏过程中,诱导型NOS对二期痛阈影响显著.