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101.
目的分析在动脉粥样硬化状态下过氧化物酶体增殖物激活受体激动剂(PPARl)吡咯列酮对肝细胞、腹腔巨噬细胞ATP结合盒转运子AI(ATP binding cassette transporter 1,ABCA1)、B族I型清道夫受体(Scavenger receptorclass BtypeI,sR—BI)及其[3H]胆固醇转出率、血浆炎性因子水平的影响,探讨吡咯列酮在胆固醇逆向转运过程中对HDL功能的调节及其抗动脉粥样硬化的机制。方法将30只雄性日本大耳兔随机分为3组。(1)对照组(n=10):正常饮食喂养;(2)动脉粥样硬化(AS)组(n=10):单纯喂高胆固醇饲料;(3)吡咯列酮组(n=10):高胆固醇饮食的基础上予以喂服吡咯列酮。20周后测定兔血脂、外周肝细胞以及腹腔巨噬细胞表面ABCAl和SR-BI的表达、胆固醇转出率以及血清炎性因子浓度。结果与正常对照组相比,AS组肝细胞和腹腔巨噬细胞的ABCA1、SR—B1及[3H]胆固醇醇转出率表达均明显降低,其差异均有统计学意义;与AS组相比,吡咯列酮组肝细胞和腹腔巨噬细胞的ABCA1、SR.B1、[3H]胆固醇醇转出率表达均显著升高,其差异均有统计学意义。结论吡格列酮可通过增加腹腔巨噬细胞、肝细胞ABCA1和SR-BI的表达,提高[3H]胆固醇醇转出率,并且上调血清炎性因子的水平,共同促进RCT,增加HDL功能,抑制AS进展。 相似文献
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H. C. Yu S. F. Feng P. L. Chao A. M. Y. Lin 《Neuropathology and applied neurobiology》2010,36(7):612-622
H. C. Yu, S. F. Feng, P. L. Chao and A. M. Y. Lin (2010) Neuropathology and Applied Neurobiology 36, 612–622 Anti‐inflammatory effects of pioglitazone on iron‐induced oxidative injury in the nigrostriatal dopaminergic system Aims: Transition metals, oxidative stress and neuroinflammation have been proposed as part of a vicious cycle in central nervous system neurodegeneration. Our aim was to study the anti‐inflammatory effect of pioglitazone, a peroxisome proliferative activated receptor‐γ agonist, on iron‐induced oxidative injury in rat brain. Methods: Intranigral infusion of ferrous citrate (iron) was performed on anaesthetized rats. Pioglitazone (20 mg/kg) was orally administered. Oxidative injury was investigated by measuring lipid peroxidation in the substantia nigra (SN) and dopamine content in the striatum. Western blot assay and DNA fragmentation were employed to study the involvement of α‐synuclein aggregation, neuroinflammation as well as activation of endoplasmic reticulum (ER) and mitochondrial pathways in iron‐induced apoptosis. Results: Intranigral infusion of iron time‐dependently increased α‐synuclein aggregation and haem oxygenase‐1 levels. Furthermore, apoptosis was demonstrated by TUNEL‐positive cells and DNA fragmentation in the iron‐infused SN. Systemic pioglitazone was found to potentiate iron‐induced elevation in nuclear peroxisome proliferative activated receptor‐γ levels. However, pioglitazone inhibited iron‐induced α‐synuclein aggregation, elevations in interleukin‐1β and interleukin‐6 mRNA levels as well as increases in oxygenase‐1, cyclo‐oxygenase II, nitric oxide synthase and ED‐1 protein levels, an indicator of activated microglia. Moreover, iron‐induced DNA laddering as well as activation of ER and mitochondrial pathways were attenuated by pioglitazone. In addition, pioglitazone decreased iron‐induced elevation in lipid peroxidation in the infused SN and depletion in striatal dopamine level. Conclusions: Our results suggest that pioglitazone prevents iron‐induced apoptosis via both ER and mitochondrial pathways. Furthermore, inhibition of α‐synuclein aggregation and neuroinflammation may contribute to the pioglitazone‐induced neuroprotection in central nervous system. 相似文献
106.
Amyloid is essential but insufficient for Alzheimer causation: addition of subcellular cofactors is required for dementia 下载免费PDF全文
Jeffrey Fessel 《International journal of geriatric psychiatry》2018,33(1):e14-e21
Objective
The aim of this study is to examine the hypotheses stating the importance of amyloid or of its oligomers in the pathogenesis of Alzheimer's disease (AD).Methods
Published studies were examined.Results
The importance of amyloid in the pathogenesis of AD is well established, yet accepting it as the main cause for AD is problematic, because amyloid‐centric treatments have provided no clinical benefit and about one‐third of cognitively normal, older persons have cerebral amyloid plaques. Also problematic is the alternative hypothesis that, instead of amyloid plaques, it is oligomers of amyloid precursor protein that cause AD.Evidence is presented suggesting amyloid/oligomers as necessary but insufficient causes of the dementia and that, for dementia to develop, requires the addition of cofactors known to be associated with AD. Those cofactors include several subcellular processes: mitochondrial impairments; the Wnt signaling system; the unfolded protein response; the ubiquitin proteasome system; the Notch signaling system; and tau, calcium, and oxidative damage.Conclusions
A modified amyloid/oligomer hypothesis for the pathogenesis of AD is that activation of one or more of the aforementioned cofactors creates a burden of functional impairments that, in conjunction with amyloid/oligomers, now crosses a threshold of dysfunction that results in clinical dementia. Of considerable importance, several treatments that might reverse the activation of some of the subcellular processes are available, for example, lithium, pioglitazone, erythropoietin, and prazosin; they should be given in combination in a clinical trial to test their safety and efficacy. © 2017 John Wiley & Sons, Ltd. 相似文献107.
The rising incidence of obesity and insulin resistance to epidemic proportions has closely paralleled the surge in the prevalence of diabetes and outpaced therapeutic advances in diabetes prevention and treatment. Current evidence points to obesity induced oxidative stress and chronic inflammation as the common denominators in the evolution of insulin resistance and diabetes. Of all the hypoglycemic agents in the pharmacological arsenal against diabetes, thiazolidinediones, in particular pioglitazone, as well as metformin appear to have additional effects in ameliorating oxidative stress and inflammation; rendering them attractive tools for prevention of insulin resistance and diabetes. In addition to their hypoglycemic and lipid modifying properties, pioglitazone and metformin have been shown to exert anti-oxidative and anti-inflammatory effects in vascular beds, potentially slowing the accelerated atherosclerosis in diabetes, which is the major cause of morbidity and mortality in the affected population. The combination of pioglitazone and metformin would thus appear to be an effective pharmacological intervention in prevention and treatment of diabetes. Finally, this review will address the currently available evidence on diabetic cardiomyopathy and the potential role of combination therapy with pioglitazone and metformin. 相似文献
108.
Erdmann E Dormandy J Wilcox R Massi-Benedetti M Charbonnel B 《Vascular health and risk management》2007,3(4):355-370
Patients with type 2 diabetes face an increased risk of macrovascular disease compared to those without. Significant reductions in the risk of major cardiovascular events can be achieved with appropriate drug therapy, although patients with type 2 diabetes remain at increased risk compared with non-diabetics. The thiazolidinedione, pioglitazone, is known to offer multiple, potentially antiatherogenic, effects that may have a beneficial impact on macrovascular outcomes, including long-term improvements in insulin resistance (associated with an increased rate of atherosclerosis) and improvement in the atherogenic lipid triad (low HDL-cholesterol, raised triglycerides, and a preponderance of small, dense LDL particles) that is observed in patients with type 2 diabetes. The recent PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) study showed that pioglitazone can reduce the risk of secondary macrovascular events in a high-risk patient population with type 2 diabetes and established macrovascular disease. Here, we summarize the key results from the PROactive study and place them in context with other recent outcome trials in type 2 diabetes. 相似文献
109.
H. MIESZCZANSKA N. K. KABA† C. W. FRANCIS† J. E. GERICH‡ R. DODIS‡ K. Q. SCHWARZ R. P. PHIPPS§ B. H. SMITH† M. LEE S. MESSING¶ M. B. TAUBMAN 《Journal of thrombosis and haemostasis》2007,5(5):942-949
OBJECTIVES: To evaluate the effects of pioglitazone on insulin sensitivity and levels of biomarkers associated with thrombotic risk in overweight and obese, non-diabetic subjects with coronary artery disease. BACKGROUND: Little information is available regarding the effects of thiazolidinediones in the absence of diabetes. Further, although postprandial hyperlipemia is a risk factor for cardiovascular diseases, there is limited information about the postprandial effects. METHODS: Twenty overweight and obese, non-diabetic patients with coronary artery disease were enrolled in a randomized, placebo-controlled, double-blind study. Subjects were on atorvastatin for the duration of the study and received either placebo or pioglitazone (45 mg day(-1)) for 12 weeks and then crossed over to the alternative therapy for an additional 12 weeks. Insulin sensitivity, fasting and postprandial levels of lipid, hemostatic, and inflammatory variables were measured, and endothelial function was assessed. RESULTS: Insulin sensitivity improved from 0.03 micromol kg(-1) x min pM(-1) on placebo to 0.04 on pioglitazone (P = 0.0002), and there were decreases in fasting levels of factor (F) VII:C (102 +/- 17% to 92 +/- 18%, P = 0.001), FVII:Ag (68 +/- 12% to 60 +/- 14%, P = 0.01) and in von Willebrand factor (VWF) (174 +/- 94% to 142 +/- 69%, P = 0.01). Pioglitazone lowered postprandial levels of FVII:Ag, FVII:C, plasminogen activator inhibitor-1, VWF, and triglycerides, and increased high-density lipoproteins (+9%, P = 0.02). CONCLUSIONS: Pioglitazone improves insulin sensitivity and favorably modifies fasting and postprandial lipid, hemostatic and inflammatory markers of the metabolic syndrome in overweight and obese non-diabetic patients with coronary artery disease. 相似文献
110.
L. M. Hettihewa S. S. Jayasinghe K. G. Imendra T. P. Weerarathna 《International journal of diabetes in developing countries.》2008,28(1):26-30