Comparison of the effects of pioglitazone and rosiglitazone on macrophage foam cell formation

In order to elucidate the antiatherogenic effects of pioglitazone (a peroxisome proliferator-activated receptor [PPAR]gamma agonist with PPARalpha agonistic activity) and rosiglitazone (a more selective PPARgamma agonist), we examined gene expression and cholesteryl ester accumulation in THP-1-derived macrophages. Pioglitazone enhanced the mRNA expression of the proatherogenic factors CD36 and adipophilin, but was approximately 10 times less potent than rosiglitazone. The potencies of the two agents appeared to correspond to their PPARgamma agonistic activities in this respect. However, both agents were similarly potent in enhancing the mRNA expression of the antiatherogenic factors liver X receptor alpha and ATP-binding cassette-transporter A1. Furthermore, both agents enhanced cholesteryl ester hydrolase mRNA expression and inhibited acyl-CoA cholesterol acyltransferase-1 mRNA expression and cholesteryl ester accumulation in macrophages. In this respect, their potencies appeared to correspond to their PPARalpha agonistic activities. These results suggest that pioglitazone has an equally beneficial effect on antiatherogenic events to rosiglitazone, despite being almost 10 times less potent than a PPARgamma agonist.     

The PPAR-gamma activator, Rosiglitazone, inhibits actin polymerisation in monocytes: involvement of Akt and intracellular calcium

Monocyte hyperactivation as seen in diabetes results in increased cytoskeletal rigidity and reduced cell deformability leading to microchannel occlusions and microvascular complications. The thiazolidinediones (TZDs) are PPAR-gamma agonists that have been reported to exert beneficial non-metabolic effects on the vasculature. This study demonstrates that the TZD, Rosiglitazone, significantly reduces f-MLP-induced actin polymerisation in human monocytic cells (p < 0.05). Two of the key signalling processes known to be involved in the regulation of cytoskeletal remodelling were investigated: PI(3)K-dependent Akt phosphorylation and intracellular calcium concentration [Ca(2+)](i). The PI(3)K inhibitor, Wortmannin, ameliorated f-MLP-induced actin polymerisation (p < 0.05), while the Ca(2+) sequestration inhibitor, thapsigargin, induced actin depolymerisation (p < 0.05), confirming the involvement of both processes in cytoskeletal remodelling. Rosiglitazone significantly reduced f-MLP activation of Akt (p < 0.05), and significantly increased [Ca(2+)](i) in both resting and f-MLP-stimulated cells (p < 0.05). Therefore, Rosiglitazone interacts with signalling events downstream of occupancy of the f-MLP receptor, to modulate cytoskeletal remodelling in a PPAR-gamma-independent manner. To our knowledge, these results are the first to present evidence that a PPAR-gamma agonist can modulate actin remodelling in monocytes, and may therefore be protective against microvascular damage in diabetes.     

Rosiglitazone is not associated with an increased risk of bladder cancer

BackgroundWhether rosiglitazone may increase bladder cancer risk has not been extensively investigated.MethodsThe reimbursement databases of all Taiwanese diabetic patients under oral anti-diabetic agents or insulin from 1996 to 2009 were retrieved from the National Health Insurance. An entry date was set at 1 January 2006 and a total of 885,236 patients with type 2 diabetes were followed up for bladder cancer incidence till end of 2009. Incidences for ever-users, never-users and subgroups of rosiglitazone exposure (using tertile cutoffs of time since starting rosiglitazone, duration of therapy and cumulative dose) were calculated and hazard ratios estimated by Cox regression.ResultsThere were 102,926 ever-users and 782,310 never-users, respective numbers of incident bladder cancer 356 (0.35%) and 2753 (0.35%), and respective incidence 98.3 and 101.6 per 100,000 person-years. The overall hazard ratios (95% confidence intervals) did not show significant association in unadjusted model [0.969 (0.867, 1.082)] and models adjusted for age and sex [0.983 (0.880, 1.098)] or all covariates [0.980 (0.870, 1.104)]. Neither the P values for the hazard ratios for the different categories of the dose–responsive parameters, nor their P-trends were significant.ConclusionsRosiglitazone does not increase the risk of bladder cancer.     

白腐菌木质素降解酶及其在木质素降解过程中的相互作用

木质素是一类不易降解的生物物质,在自然界中,白腐真菌对木质素的降解能力最强.白腐真菌降解木质素主要依靠分泌的三种酶:木质素过氧化物酶(Lip)、锰过氧化物酶(MnP)和漆酶(Lac).对白腐真菌分泌的三种木质素降解酶在性质、分布等方面进行了比较,系境地介绍三种木质素降解酶的催化作用,并阐述其在木质素降解过程中的相互作用.     

Effects of PBN and OKN007 in rodent glioma models assessed by 1H MR spectroscopy

Gliomas, the most common primary brain tumors in adults, have a poor outcome. PBN (α-phenyl-tert-butylnitrone) and OKN007 (2,4-disulfophenyl-PBN) are nitrones that have demonstrated beneficial effects in many aging diseases. In this study, we evaluated the anti-tumor effects of PBN and OKN007 in several rodent glioma models (C6, RG2, and GL261) by assessing metabolite alterations with magnetic resonance spectroscopy (MRS). PBN or OKN007 was administered in drinking water before or after tumor formation. MR imaging and single-voxel point-resolved spectroscopy were done to assess tumor morphology and metabolites, after therapy. Major metabolite ratios (choline, N-acetylaspartate, and lipid (methylene or methyl), all compared to creatine), as well as quantification of individual metabolite concentrations, were assessed. Nitrones induced tumor metabolism changes that resulted in restoring major metabolite ratios close to their normal levels, in the glioma regression phase. Nitrone treatment decreased the lipid (methylene)-to-creatine ratio, as well as the estimated concentration of lipid (methylene) significantly. Alterations in lipids can be a useful marker for the evaluation of the efficacy associated with treatment and were found in this study to be related to the reduction of necrosis, but not apoptosis. OKN007 was more effective than PBN when administered after tumor formation in the C6 glioma model. In conclusion, ¹H MRS and conventional MRI are useful methods to assess and follow the response of varied glioma models to anti-tumor treatments.     

Peroxisome proliferator-activated receptor α agonists modulate Th1 and Th2 chemokine secretion in normal thyrocytes and Graves' disease

Until now, no data are present about the effect of peroxisome proliferator-activated receptor (PPAR)α activation on the prototype Th1 [chemokine (C–X–C motif) ligand (CXCL)10] (CXCL10) and Th2 [chemokine (C–C motif) ligand 2] (CCL2) chemokines secretion in thyroid cells.The role of PPARα and PPARγ activation on CXCL10 and CCL2 secretion was tested in Graves' disease (GD) and control primary thyrocytes stimulated with interferon (IFN)γ and tumor necrosis factor (TNF)α.IFNγ stimulated both CXCL10 and CCL2 secretion in primary GD and control thyrocytes. TNFα alone stimulated CCL2 secretion, while had no effect on CXCL10. The combination of IFNγ and TNFα had a synergistic effect both on CXCL10 and CCL2 chemokines in GD thyrocytes at levels comparable to those of controls. PPARα activators inhibited the secretion of both chemokines (stimulated with IFNγ and TNFα) at a level higher (for CXCL10, about 60–72%) than PPARγ agonists (about 25–35%), which were confirmed to inhibit CXCL10, but not CCL2.Our data show that CCL2 is modulated by IFNγ and TNFα in GD and normal thyrocytes. Furthermore we first show that PPARα activators inhibit the secretion of CXCL10 and CCL2 in thyrocytes, suggesting that PPARα may be involved in the modulation of the immune response in the thyroid.     

罗格列酮对2型糖尿病合并急性冠脉综合征患者血清TGF-β1及IL-1β 的影响

目的:观察罗格列酮对2型糖尿病合并急性冠脉综合征患者血清转化生长因子-β1(TGF-β1)及白细胞介素-1β(IL-1β)的影响。方法:116例2型糖尿病合并急性冠脉综合征患者,随机分为罗格列酮治疗组(n=58)和常规治疗组(n=58)。检测两组患者治疗前后空腹血糖、血脂及血清TGF-β1、IL-1β的变化。结果:治疗前两组患者空腹血糖、血脂及血清TGF-β1、IL-1β的水平无显著差异(P>0.05);治疗4月后,两组患者空腹血糖、血脂无显著差异,血清IL-1β较治疗前下降(P<0.01),罗格列酮组较常规治疗组下降明显,两组间差异显著(P<0.05);治疗后血清TGF-β1较治疗前上升(P<0.05),罗格列酮组与常规治疗组比较,差异显著(P<0.05)。结论:罗格列酮能调控糖尿病合并急性冠脉综合征患者炎症介质和抗炎因子的分泌,可能具有改善动脉粥样硬化的作用。     

Rosiglitazone treatment reduces hippocampal neuronal damage possibly through alleviating oxidative stress in chronic cerebral hypoperfusion

Oxygen free radicals and lipid peroxidation may play significant roles in the progress of injury induced by chronic cerebral hypoperfusion of the central nervous system. Rosiglitazone, a well known activator of PPARγ, has neuroprotective properties in various animal models of acute central nervous system damage. In the present study, we evaluate the possible impact of rosiglitazone on chronic cerebral hypoperfused-rats in regard to the levels of oxidative stress, reduced glutathione, and hippocampal neuronal damage. Chronic cerebral hypoperfusion was generated by permanent ligation of both common carotid arteries of Wistar rats for one month. Animals in treatment group were given rosiglitazone orally at doses of 1.5, 3, or 6mg/kg per day of the 1month duration. The treatment significantly lowered the levels of both malondialdehyde and neuronal damage, while elevated the reduced glutathione level markedly. These findings suggest that the beneficial effect of rosiglitazone on hypoperfusion-induced hippocampal neuronal damage might be the result of inhibition of oxidative insult.     

PPARγ受体激动剂罗格列酮治疗的慢性阻塞性肺疾病样大鼠肺组织细胞因子的变化

目的研究过氧化物酶体增殖物激活的受体γ（PPARγ）激动剂罗格列酮对慢性阻塞性肺疾病（COPD）样大鼠肺组织、支气管肺泡灌洗液（BALF）中白介素-8（IL-8）、肿瘤坏死因子-α（TNF-α）和白介素-4（IL-4）的影响。方法被动吸烟和气管内滴注脂多糖（LPS）复制大鼠模型并随机分为模型组和罗格列酮治疗组。制备肺组织匀浆和支气管肺泡灌洗液,用放免法检测IL-8、TNF-α,用ELISA法测IL-4。结果与模型组比较罗格列酮治疗组大鼠肺组织IL-8、TNF-α含量降低而IL-4含量增加。结论 PPAR-γ通路激活对COPD中的炎症反应有负调节作用。