罗格列酮通过激活PPARγ改善肺动脉高压大鼠肺动脉内皮依赖性舒张功能

 目的：探索过氧化物酶体增殖物激活受体γ（PPARγ）激动剂罗格列酮对肺动脉高压大鼠模型肺动脉血管内皮功能的影响。方法：（1）SD大鼠40只,分为正常对照组、模型组、罗格列酮组和罗格列酮+GW9662（PPARγ拮抗剂）干预组,每组10只,以野百合碱（60 mg/kg）一次性皮下注射复制肺动脉高压大鼠模型,再灌胃给予罗格列酮（2.0 mg·kg-1·d-1）或罗格列酮 + GW 9662（0.3 mg·kg-1·d-1）干预。4周后,取血浆测一氧化氮（NO）及内皮素-1（ET-1）的水平,分离肺动脉二级分支,以微血管张力测定仪测定肺动脉血管功能变化情况。（2）体外培养人肺动脉内皮细胞株（HPAECs）,探讨罗格列酮对HPAECs　NO生成的影响。结果：罗格列酮可显著改善肺动脉高压大鼠血管内皮依赖性舒张功能,但不能显著改善非内皮依赖性舒张功能;罗格列酮干预可降低血浆ET-1水平,升高NO水平;但罗格列酮的以上作用在同时给予PPARγ拮抗剂GW9662时显著被减弱。体外实验证实,罗格列酮可显著增加HPAECsf的NO生成,但该作用同样可被GW9662所阻断。结论：罗格列酮通过激活PPARγ改善肺动脉高压大鼠的血管内皮依赖性舒张功能可能是其治疗肺动脉高压的基础。     

Induction of PPAR gamma mRNA and protein expression by rosiglitazone in chronic cyclosporine nephropathy in the rat

PURPOSE: We recently reported that rosiglitazone (RGTZ), a peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, has a protective effect against cyclosporine (CsA)- induced renal injury. Here we report the effect of RGTZ on peroxisome proliferator-activated receptor gamma (PPARgamma) expression in an experimental model of chronic cyclosporine (CsA) nephropathy. MATERIALS AND METHODS: Chronic CsA nephropathy was induced in Sprague-Dawley rats by administering CsA (15mg/kg per day) for 28 days, and control rats were treated with vehicle (VH group, olive oil 1mL/kg per day) for 28 days. RGTZ (3mg/kg) was concurrently administered via gavage to the CsA and VH groups. Expression of PPARgamma mRNA and protein was evaluated with RT-PCR, immunohistochemistry, and immunoblotting. RESULTS: PPARgamma mRNA expression was similar to the level of PPARgamma protein constitutively expressed in the kidneys of the VH treated rats, with expression in the glomerular epithelial, distal tubular cells, and collecting tubular cells. PPARgamma protein expression in CsA-treated rat kidneys was significantly less than in the VH group. However, concomitant administration of RGTZ restored PPARgamma protein expression in the kidneys of the CsA- reated rats. CONCLUSION: Exogenous administration of RGTZ treatment upregulates PPARgamma expression and that this mechanism may play a role in protecting against CsA-induced renal injury.     

罗格列酮通过抑制RANKL及p-ERK活化抑制类风湿关节炎破骨细胞的分化及功能

目的:探讨罗格列酮(RSG)对类风湿关节炎(RA)成纤维样滑膜细胞(FLS)介导的破骨细胞(Oc)分化及功能的影响及其可能机制。方法:活动期RA患者滑膜体外分离培养FLS,与健康人外周血单核细胞(MNC)共培养,不同浓度RSG(0、5、10和15μmol/L)干预,抗酒石酸酸性磷酸酶(TRAP)染色鉴定Oc并计数;甲苯胺蓝染色和图像分析系统计算骨吸收陷窝面积;Real-time PCR检测共培养体系RANKL和OPG的mRNA表达,Western blot检测RANKL、OPG、p-ERK、p-p38和p-JNK的蛋白含量。结果:与不加RSG组比较,15μmol/L RSG干预后Oc的数量明显减少(P0.01),骨吸收陷窝面积也减少(P0.05);共培养体系RANKL的mRNA及蛋白表达明显降低,OPG的mRNA及蛋白表达明显升高(P0.01);p-ERK的蛋白含量明显降低(P0.05),p-p38及p-JNK的蛋白含量则不受影响。结论:RSG通过抑制RANKL及p-ERK活化影响RA关节微环境中组织细胞与免疫细胞的相互作用,从而抑制Oc分化及骨吸收功能。     

Endocrine and metabolic effects of rosiglitazone in overweight women with PCOS: a randomized placebo-controlled study

BACKGROUND: The objective of the study was to assess the therapeutic effects of rosiglitazone in overweight women with polycystic ovary syndrome (PCOS). METHODS: A double-blind, placebo-controlled study was conducted on 30 (BMI > 25 kg/m2, mean age 29.1 +/- 1.2 years) overweight women with PCOS treated with rosiglitazone or placebo for 4 months. Waist-to-hip ratios (WHRs), serum concentrations of sex hormones and binding proteins, blood glucose, serum insulin and serum C-peptide during a 75-g oral glucose tolerance test (OGTT), first-phase insulin secretion as determined by an intravenous glucose tolerance test (IVGTT), M values (expressing insulin sensitivity using a euglycaemic clamp) and calorimetric data were assessed at 0 and 4 months of treatment. RESULTS: Rosiglitazone improved menstrual cyclicity, increased serum sex hormone-binding globulin (SHBG) levels and decreased serum levels of androstenedione, 17-hydroxyprogesterone (17-OHP), dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulphate (DHEA-S). Glucose tolerance [expressed as AUC(glucose) during the OGTT] improved (P = 0.002) and peripheral insulin response (expressed as AUC(insulin)) decreased (P = 0.004) in the rosiglitazone group (ROSI group). M value improved in the ROSI group from 33.4 +/- 3.27 to 40.0 +/- 5.51 micromol/kg min (P = 0.04). CONCLUSION: Rosiglitazone, by improving menstrual cyclicity, hyperandrogenism, insulin resistance and hyperinsulinaemia, represents an alternative treatment for overweight anovulatory women with PCOS and no pregnancy desire.     

Rosiglitazone, an agonist of peroxisome proliferator-activated receptor γ, reduces pulmonary inflammatory response in a rat model of endotoxemia

Objective: The effect of rosiglitazone, a potent peroxisome proliferator-activated receptor γ (PPAR-γ) agonist, on pulmonary inflammation in endotoxemia was investigated. Materials and methods: Male Wistar rats were given either lipopolysaccharide (LPS, 6 mg/kg i.v.) or saline, pretreated with rosiglitazone (0.3 mg/kg i.v.) or its vehicle (dimethyl sulphoxide) 30 min before LPS. The selective PPAR-γ antagonist GW9662 (0.3 mg/kg i.v.) was given 20 min before rosiglitazone. Wet/dry weight (W/D) ratio, myeloperoxidase (MPO) activity, malondialdehyde (MDA) as well as TNF-α and CINC-1 concentrations were measured in lung tissues 4 h after LPS injection. Expression of ICAM-1, NF-κB p65 and PPAR-γ were also determined by immunohistochemistry or Western blot analysis. Results: Rosiglitazone pretreatment significantly attenuated the increases in W/D ratio, MPO activity and MDA levels, and reduced pulmonary overproduction of TNF-α and CINC-1 as well as expression of ICAM-1 following endotoxemia. Rosiglitazone also inhibited the nuclear localization of NF-κB and up-regulated the expression of PPAR-γ protein. The specific PPAR-γ antagonist GW9662 abolished the effect of rosiglitazone. Conclusion: These findings suggest that PPAR-γ agonists might be used as therapeutic agents in the therapy of inflammatory lung injury related to endotoxemia. Received 8 January 2005; returned for revision 6 July 2005; returned for final revision 20 July 2005; accepted by M. Katori 31 July 2005     

Rosiglitazone and ethinyl estradiol/cyproterone acetate as single and combined treatment of overweight women with polycystic ovary syndrome and insulin resistance

BACKGROUND: Few studies have evaluated insulin sensitizers in comparison/association with oral contraceptives (OC) in women with polycystic ovary syndrome (PCOS) with insulin resistance (IR). This study assessed the effects of a thiazolidinedione versus an anti-androgenic estrogen-progestin followed by their sequential combinations in overweight PCOS women. METHODS AND RESULTS: Twenty-eight candidates in whom elevated insulin was not normalized after 4 months of diet were randomly assigned to 6 months of rosiglitazone 4 mg/day or to ethinyl estradiol 35 mg/cyproterone acetate 2 mg (EE/CPA: 21/28 days cycle). Each group then received both medications for another 6 months. Rosiglitazone reduced insulin, IR indices [homeostasis model assessment (HOMA) and quantitative sensitivity check index (QUICKI)] and the insulin area under the curve in response to an oral glucose tolerance test (OGTT), but had limited effect on lipids, androgens and hirsutism. EE/CPA did not modify insulin and OGTT response but increased high-density lipoprotein cholesterol and triglycerides and decreased androgens and hirsutism. Similar changes occurred during combined treatments. End results were highly significant in combined groups without noticeable side-effects or changes in safety parameters. CONCLUSIONS: In obese PCOS women with high insulin not corrected by diet, the combination of rosiglitazone and EE/CPA may be used to achieve complementary beneficial effects on endocrine-metabolic anomalies and clinical symptoms.     

Effect of rosiglitazone on cardiac electrophysiology, infarct size and mitochondrial function in ischaemia and reperfusion of swine and rat heart

Rosiglitazone, a peroxisome proliferator-activated receptor γ agonist, has been used to treat type 2 diabetes. Despite debates regarding its cardioprotection, the effects of rosiglitazone on cardiac electrophysiology are still unclear. This study determined the effect of rosiglitazone on ventricular fibrillation (VF) incidence, VF threshold (VFT), defibrillation threshold (DFT) and mitochondrial function during ischaemia and reperfusion. Twenty-six pigs were used. In each pig, either rosiglitazone (1 mg kg(-1)) or normal saline solution was administered intravenously for 60 min. Then, the left anterior descending coronary artery was ligated for 60 min and released to promote reperfusion for 120 min. The cardiac electrophysiological parameters were determined at the beginning of the study and during the ischaemia and reperfusion periods. The heart was removed, and the area at risk and infarct size in each heart were determined. Cardiac mitochondria were isolated for determination of mitochondrial function. Rosiglitazone did not improve the DFT and VFT during the ischaemia-reperfusion period. In the rosiglitazone group, the VF incidence was increased (58 versus 10%) and the time to the first occurrence of VF was decreased (3 ± 2 versus 19 ± 1 min) in comparison to the vehicle group (P < 0.05). However, the infarct size related to the area at risk in the rosiglitazone group was significantly decreased (P < 0.05). In the cardiac mitochondria, rosiglitazone did not alter the level of production of reactive oxygen species and could not prevent mitochondrial membrane potential changes. Rosiglitazone increased the propensity for VF, and could neither increase defibrillation efficacy nor improve cardiac mitochondrial function.     

Wi-Fi decreases melatonin protective effect and increases hippocampal neuronal damage in pentylenetetrazole induced model seizures in rats

AimEpilepsy is a common brain disorder in which the seizures could cause a neuronal loss in the hippocampus. Oxidative stress has an important role in the pathology of epilepsy. Some studies indicate that Wi-Fi increases oxidative stress and suppresses antioxidant systems. The aim of this study is to investigate the effect of Wi-Fi on melatonin anticonvulsive effect and oxidative damage in pentylenetetrazole-induced epileptic seizures in rats.MethodsIn our study, we used 30 male Wistar Albino rats, 230?250 grams of the body weight. The animals were divided into five groups as control, saline (1 ml/kg/day olive oil for 30 days), Wi-Fi (12 h/day for 30 days), melatonin (10 mg/kg/day for 30 days) and melatonin + Wi-Fi (10 mg/kg/day +12 h/day for 30 days). In the thirtieth day, thirty minutes after the last drugs administration at the indicated doses, PTZ in 45 mg/kg was administered to induce epileptic seizure. The animals were observed for 30 min during the seizure stages (according to the Racine Scale) and first myoclonic jerk times (FMJ). Twenty-four hours after PTZ injection, brain tissues were removed for biochemical and histopathological evaluation. The hippocampal Cornu Ammonis (CA) 1, CA3 and DG (dentate gyrus) regions were histopathologically evaluated in terms of a neuronal damage in addition that oxidative stress markers (total antioxidant status (TAS), total oxidant status (TOS) and oxidative stress index (OSI)) were measured in brain tissues.ResultsWi-Fi was not found to affect behavioral changes associated with epilepsy (p > 0.05). However, Wi-Fi reduced anticonvulsive and antioxidant effect of melatonin (p < 0.05). Moreover, Wi-Fi increased neuronal damage in hippocampus (p < 0.05).ConclusionWi-Fi did not directly affect epileptic seizures. Nevertheless, it inhibits the positive effects of melatonin on epilepsy and it also has negative effects on hippocampal neuronal damage. These effects of Wi-Fi may occur via oxidative pathways.     

Alterations in the half-life and clearance of IgG during therapy with intravenous γ-globulin in 16 patients with severe primary humoral immunodeficiency

Published studies of the metabolism of human IgG using trace amounts of radiolabeled IgG demonstrated that the elimination of native IgG followed first-order kinetics but that the half-life of IgG was shortest in patients with the highest serum concentrations of IgG. To evaluate the effect of increasing the serum concentration of IgG on the metabolism of IgG, we determined the half-life and clearance of IgG and tetanus antibody in 16 patients with severe primary humoral immunodeficiency diseases while they received several doses of intravenous -globulin (IVIG). Each patient received 100 mg/kg of IVIG each month and the half-life and clearance of IVIG were determined by following the decline in the serum IgG concentration. The dose of IVIG was adjusted to give a minimum IgG level of 200 mg/dl and the half-life was reevaluated. The dose was again adjusted to give minimum concentrations of 450 mg/dl and two additional studies were performed. Mean doses of IVIG infused increased from 100 to 346 mg/kg. The mean trough serum IgG concentration was 191 mg/dl on the standard dose and increased to 427 mg/dl at the highest dose. The serum half-lives of IgG were highly variable, ranging from 22 to 96 days. The mean decreased from 43 days in the first to 33 days in the third and fourth studies, and the clearances of IgG increased from 1.8339 to 2.4302 mg/kg/day, but the differences were not statistically significant. Patients with the highest serum IgG concentrations tended to have the longest half-lives, suggesting that intrinsic IgG production might falsely prolong the calculated half-life of IgG. However, it was possible to determine the half-life in these patients by measuring the decline in tetanus antibody. The half-life measured by this technique in the third and fourth studies was 27 and 36 days and the clearances were 2.988 and 3.648 ml/kg/day. Knowledge of the metabolism of IgG in these patients may lead to more appropriate guidelines for determination of dosage.     

Rosiglitazone reverses cardiac adverse remodeling (fibrosis and vascularization) in perinatal low protein rat offspring

Rosiglitazone, a PPAR gamma agonist, is an antidiabetic drug that shows secondary beneficial actions on cardiovascular system. Our study is centered on myocardial remodeling in maternal protein restriction offspring, focusing on fibrosis and vascularization. Wistar rat dams received one of the two diets: normal (19% protein; NP) or low protein (5% protein; LP) during gestation and lactation. Three-month-old male offspring were divided into four groups: NP treated with rosiglitazone (NPR, 5 mg/kg/day); untreated NP (NP); LP treated (LPR); untreated LP (LP) until six months. Blood pressure (BP) was higher in LP, but rosiglitazone reduced BP at the first week of treatment in LPR. Rosiglitazone had beneficial effects on fibrosis (less than 23%, P < 0.05) and vascularization (plus 57% of capillary/cardiomyocyte ratio, P < 0.01) compared with LP offspring, independently of blood glucose. Multivariate analysis classified 95% of groups, and LPR offspring showed values close to those of NP offspring. Rosiglitazone showed beneficial effects on rat offspring programmed by low protein diet during gestation decreasing cardiac fibrosis and enhancing myocardial vascularization. These results are significant in translational medicine for patients with chronic diseases in adult life and increased cardiovascular risk.     

Promotion of colon tumors in C57BL/6J-APC(min)/+ mice by thiazolidinedione PPARgamma agonists and a structurally unrelated PPARgamma agonist

Thiazolidinedione PPARgamma agonists (troglitazone and rosiglitazone) were previously shown to promote colon tumor formation in C57BL/6J-APC(min)/+ mice, a model for human familial adenomatous polyposis. This study was conducted to determine if another thiazolidinedione PPARgamma agonist, pioglitazone, and a PPARgamma agonist structurally unrelated to the thiazolidinedione family, NID525, (a tetrazole-substituted phenoxymethylquinolone), would also promote colon tumors in this mouse model. Mice were treated in-feed with the thiazolidinediones troglitazone (150 mg/kg/day), rosiglitazone (20 mg/kg/day), or pioglitazone (150 mg/kg/day), or with NID525 (150 mg/kg/day) for 8 weeks. An increased incidence in colon tumors compared to controls was observed for all of the thiazolidinedione-treated groups as well as the NID525-treated group. These results indicate that the tumor-promoting effect of PPARgamma agonists in the colon of C57BL/6J-APC(min)/+ mice is likely related to the pharmacological activity of this group of drugs and not the thiazolidinedione structure.     

Effect of melatonin in the prevention of post-operative adhesion formation in a rat uterine horn adhesion model

BACKGROUND: Our main aim was to investigate the effects of melatonin (ME), possibly the most powerful free-radical scavenger, on the prevention of i.p. adhesion formation in rat uterine horn. Our secondary aim was to determine whether different methods of administration of ME were beneficial. METHODS: Animals were randomly assigned into seven groups, each consisting of 13 rats. Measured serosal injury was created using a standard technique. While control and two sham groups were not given ME, two of the remaining four groups were given a single dose of 10 mg/kg (2 mg) of ME i.p. immediately after injury and 30 min prior to injury respectively. In the two other groups, ME treatment was continued daily for 5 days. All animals were killed 2 weeks after surgery and adhesions were determined and scored by a examiner blinded to the test. RESULTS: The extent, severity and total scores of adhesion were found to be significantly reduced in all of the ME treatment groups when compared with control and sham groups. There were no statistically significant differences between the treatment groups. CONCLUSIONS: This study showed that even single dose ME therapy was effective in the prevention of post- operative i.p. adhesion formation.     

针刺提高2型糖尿病模型大鼠胰岛β细胞胰岛素的表达

背景：针刺治疗2型糖尿病具有很好的疗效。 目的：观察针刺对2型糖尿病模型大鼠胰岛β细胞胰岛素表达的影响。 方法：将糖尿病模型大鼠按随机化原则分为针刺组、西药组、模型组,同时设置正常对照组。针刺组大鼠取足三里、内庭和胰俞穴给予针刺治疗,西药组用罗格列酮0.2 mg/kg灌胃,模型组用双蒸水2 mL/kg灌胃,均1次/d,连续4周。 结果与结论：①血糖：针刺组明显低于模型组、西药组(P < 0.05)。②血脂：针刺组胆固醇和三酰甘油低于模型组 (P < 0.05);高密度脂蛋白胆固醇明显高于模型组(P < 0.01)。针刺组三指标与西药组比较差异无显著性意义。③胰岛β细胞胰岛素表达：针刺组显著高于模型组和西药组(P < 0.05)。④胰岛形态：模型组与西药组胰岛结构不完整,结构破坏,胰岛素染色效果差;针刺组胰岛结构趋向完整,胰岛素染色颗粒明显。说明针刺可显著提高2型糖尿病模型大鼠胰岛β细胞胰岛素表达水平,有效改善胰岛β细胞功能。     

Effect of etodolac on type-II collagen-induced arthritis in mice

We tested the effect of etodolac on the development of type-II collagen-induced arthritis in DBA/1J mice. It was administered orally once daily for 35 days after the primary immunization with type-II collagen. Etodolac (10 mg/kg) significantly inhibited the development of signs of arthritis on day 28 to day 35. Indomethacin (1 mg/kg) also significantly inhibited it on day 29 to day 34. Radiographic examination showed that etodolac (10 mg/kg) significantly prevented the development of osteopenia, bone erosion and new bone formation of the joints on day 35, while indomethacin (1 mg/kg) significantly prevented only the development of bone erosion. Histopathological examination showed that both etodolac (10 mg/kg) and indomethacin (1 mg/kg) significantly prevented the development of synovitis, erosion of cartilage of the joints and bone destruction of the limbs on day 35. Etodolac and indomethacin did not affect the serum level of anti-type-II collagen antibodies. These results suggest that etodolac and indomethacin suppress type-II collagen-induced arthritis without affecting humoral immune responses.     

Oral l-arginine protects against cyclosporine-induced hepatotoxicity in rats

Cyclosporine A (CyA) leads to liver injury, probably by causing the production of free radicals and resulting in nitric oxide (NO) deficiency. We evaluated CyA-mediated liver damage histopathologically to determine the possible beneficial effects of L-arginine (L-Arg). In this study, 7 groups of Sprague-Dawley rats; (1) Control group; (2) 0.9% NaCl group; (3) CyA group: 7.5mg/kg/day; (4) L-Arg group: 2g/lt/day; (5) l-NAME (N-nitro-L-arginine methyl ester) group: 5mg/100ml/day; (6) CyA+L-Arg group: L-Arg (2g/lt/day)+CyA (7.5mg/kg/day); and (7) CyA+L-NAME group: CyA (7.5mg/kg/day)+L-NAME (5mg/100ml/day) were included. At the end of the treatments, animals were killed and hepatic tissues were treated for morphological (hematoxylin and eosin) and biochemical (NO and malondialdehyde, MDA) analyses, and serum was processed for biochemical (alanine transaminase (ALT), aspartate transaminase (AST), bilirubin, alkaline phosphatase (ALP) and total protein) study. The results indicated that CyA-induced hepatotoxicity was characterized by sinusoidal dilatation, hepatocellular vacuolization, neutrophilic infiltration and hepatocellular necrosis. These findings were less pronounced in the CyA+L-Arg group than CyA alone group. L-NAME group showed moderate changes. The CyA+L-NAME (Group 7) had more severe changes. We found changes in tissue NO and MDA levels. We think that the tissue damage caused by CyA is mild and reversible at the period when biochemical parameters are just starting to become abnormal and that L-Arg may have a protective effect against CyA damage on liver.     

罗格列酮抗炎作用的研究进展

罗格列酮具有增加胰岛素敏感性、降低胰岛素抵抗而调节血糖的作用,临床广泛用于糖尿病的治疗。近年发现罗格列酮还在全身多器官、多系统的急慢性炎症病变中发挥着重要的抗炎作用。探索罗格列酮抗炎作用的机制可能为炎性疾病的治疗带来新的希望。     

Persistence of SCE-inducing lesions in lymphocytes of mice exposed to diaziquone

Male C57B1/6 mice were injected i.p. with either 1.25 or 5.0 mg/kg diaziquone (AZQ) and killed at various time intervals from 1 to 99 days post treatment for examination of sister chromatid exchange (SCE) persistence in the peripheral blood lymphocytes (PBLs) and splenocytes. SCE frequencies were found to decay steeply during the first week after exposure in both PBLs and splenocytes. This pattern was followed by a slower decline to baseline over the next week. However, high-frequency cell (HFC) analysis indicates that significant numbers of HFCs persist in the PBLs through day 28 and splenocytes at day 99 post exposure. Mathematical modeling of the time-response curves indicates that the average life span of the majority of AZQ-induced SCE-producing lesions in murine PBLs and splenocytes responsive to phytohemagglutinin is between 3 and 5 days.     

罗格列酮对2型糖尿病大鼠血浆resistin的影响及对肾小球硬化的干预研究

目的： 研究罗格列酮对糖尿病大鼠血清巨噬细胞因子resistin水平的影响,探讨该药物对糖尿病肾小球硬化的干预及可能的作用机制。方法： 20只10周龄Wistar大鼠随机分为糖尿病肾病（DN）模型组和罗格列酮干预组(DN+RSG),另取10只Wistar大鼠作为正常对照组(NC)。DN和罗格列酮干预组大鼠右肾切除后经过阴茎背静脉注射35 mg/kg链脲菌素（STZ）,罗格列酮组按照10 mg·kg-1·d-1的剂量给予罗格列酮灌胃,DN组及正常对照组喂饲普通饮食。STZ注射20周后留取静脉血和24h尿,后处死大鼠并取肾组织。ELISA法检测血浆白细胞介素-1(IL-1)、肿瘤坏死因子-α (TNF-α)及resistin水平,免疫比浊法测定高敏C反应蛋白(hs-CRP),并测定24 h尿微量白蛋白、空腹血糖及肾功能水平。光镜下观察肾组织的病理改变情况,免疫组化检测肾小球转化生长因子-β1(TGF-β1) 的表达,Western blotting检测Smad2磷酸化水平。 结果： 与NC组比较,DN组大鼠血浆炎症因子IL-1、TNF-α、hs-CRP及resistin的水平均显著升高;罗格列酮干预后血浆中上述指标含量均显著低于模型组。与DN组比较,罗格列酮干预组的空腹血糖无明显变化,但24 h尿微量白蛋白定量及肾功能水平均明显下降。罗格列酮干预后肾小球内TGF-β1蛋白表达及Smad2磷酸化水平较DN组显著降低,并且其肾小球系膜增生程度也较DN组明显减轻。结论： 罗格列酮具有延缓及改善糖尿病肾小球硬化的作用,该作用可能与其降低resistin及其它炎症相关因子的表达有关。针对炎症有望控制DN的发生发展。     

Effect of FTY720, a novel immunosuppressant,on adjuvant-induced arthritis in rats

OBJECTIVE AND DESIGN: Anti-arthritic effect of FTY720, a novel immunosuppressant, was compared with those of immunosuppressants cyclosporin A and tacrolimus in adjuvant-induced arthritis in rats. MATERIAL: Male LEW rats. TREATMENT: FTY720 (0.03-0.3 mg/kg), cyclosporin A (1-10 mg/kg) or tacrolimus (0.3-3 mg/kg) were orally administered to rats for 21 days beginning on the day (day 0) of adjuvant inoculation. In addition, the anti-arthritic effect of FTY720 (0.3 mg/kg) and cyclosporin A (10 mg/kg) were evaluated by administration to animals for 5 consecutive days (days 2-6, 6-10, and 10-14). METHODS: Adjuvant-induced arthritis was produced by intradermal injection of 0.5 mg heat-killed Mycobacterium tuberculosis. Hindpaw edema was measured plethysmographically. The day of arthritis onset was determined macroscopically. Bone degradation was determined by radiography. Peripheral blood leukocytes were classified microscopically. RESULTS: All test compounds inhibited the incidence of arthritis, hindpaw edema and bone destruction. In addition, FTY720 but not cyclosporin A or tacrolimus markedly decreased the number of peripheral blood lymphocytes. FTY720 treatment on days 6 to 10 inhibited the bone destruction and hindpaw edema. CONCLUSION: These results suggest that the anti-arthritic effect of FTY720 in this adjuvant-induced arthritic model was more potent than those of cyclosporin A and tacrolimus. FTY720 administered on days 6 to 10 showed the inhibitory effect on the bone destruction and hindpaw edema. FTY720 may be effective in the treatment of rheumatoid arthritis.