PPARγ激动剂荧光探针法研究进展

过氧化物酶增殖激活受体(peroxisome proliferatoractivated receptors,PPARs)属于核激素受体家族中的配体激活受体,包括3种亚型:PPARα、PPARβ/δ和PPARγ。PPARγ具有增强机体对胰岛素敏感性,调节体内糖平衡以及脂肪分化、生成等多种生物学功能。通过荧光探针法研究PPARγ与配体结合,对研究PPARγ激动剂作用机制及筛选PPARγ激动剂具有重要的意义。本文针对新型荧光探针法探究PPARγ与配体的结合能力以及筛选PPARγ激动剂研究进行综述。     

一类新型的四氢异喹啉类PPARα/γ受体激动剂的设计、合成与活性研究

为得到更高效的PPAR(过氧化物酶体增殖激活受体)α/γ受体激动剂,设计合成了新型的四氢异喹啉类化合物,通过1H NMR、HR-MS对化合物结构进行了确证,并测定了化合物的体外PPARα/γ受体激动活性。其中化合物8a具有PPARα/γ双受体激动活性,其PPARα/γ受体激动活性与阳性对照品WY14643、罗格列酮相比活性更强。     

代谢综合征的防治靶标过氧化物酶体增殖物激活受体γ

过氧化物酶体增殖物激活受体γ(PPARγ)是核受体超家族成员PPAR之一,其配体作为胰岛素增敏剂已广泛应用于临床2型糖尿病的治疗。PPARγ亚型因基因结构的不同,而呈现组织分布和配体激活的特异性。PPARγ配体除调节糖脂代谢外,对胰岛素敏感性、动脉粥样硬化、炎症以及细胞增殖与分化都具有重要的调控作用。本文通过综述PPARγ的研究进展,初步探讨其临床应用前景以及存在的争议。     

PPARγ与骨代谢的研究进展

过氧化物酶体增殖激活受体（PPAR）是核激素受体超家族成员。PPARγ2亚型是脂肪细胞分化的主要调节因子,对骨髓干细胞的分化方向起关键调控作用,可能是引起骨质疏松的机制之一。本文综述了PPARγ与骨代谢的研究进展。     

PPARγ激活剂罗格列酮对兔动脉粥样硬化斑块消退的影响

过氧化物酶体增殖激活受体γ(PPARγ)是一个核受体,在血管壁内皮细胞、巨噬细胞/泡沫细胞及血管平滑肌细胞都有较高表达。PPARγ通过对这些细胞的调控作用,还影响着炎性因子的水平,在动脉粥样硬化(AS)疾病中发挥着重要的作用[1]。本实验通过高选择性PPARγ激动剂罗格列酮对高胆     

过氧化物酶体增殖物激活受体δ与中枢神经系统疾病

过氧化物酶体增殖物激活受体（peroxisome proliferatoractivated receptors,PPARs）是核受体超家族成员,在哺乳动物中存在3种亚型：PPARα、PPARγ和PPARδ。它们的结构相似,     

选择性PPARγ调节剂治疗二型糖尿病的分子机制研究进展

第一类胰岛素增敏剂——过氧化物酶体增殖体激活受体γ(PPARγ)激动剂噻唑烷二酮类药物(TZDs)曾在二型糖尿病(T2DM)治疗中具有不可替代的作用。但由于TZDs类药物存在增重、水肿、骨折、充血性心力衰竭等严重副作用,保留TZDs类药物的胰岛素增敏效果而无其副作用的选择性PPARγ调节剂(SPPARγM)是新型胰岛素增敏剂的发展方向。现有实验主要对SPPARγM候选分子影响PPARγ受体构象改变、受体磷酸化、受体对共调节因子的选择性募集和PPARγ下游靶基因选择性开启等几个层次的分子作用机制作了初步探讨。该文综述了SPPARγM治疗二型糖尿病的分子机制研究进展。     

PPARγ及其配体与肿瘤侵袭转移关系研究进展

过氧化物酶体增殖物激活受体(peroxisome proliferator activated receptors,PPARs)是一类由配体激活的转录因子家族,属Ⅱ型核受体超家族成员,1990年由英国科学家Isse mann和Green首先发现[1].目前已知PPAR存在三种亚型,即PPARα、PPARδ(亦称PPARβ)及PPARγ,其中对PPARγ的研究最广泛、最深入.PPARγ最初是在脂肪细胞中被发现,并发现它在脂肪细胞的形成、分化及胰岛素敏感方面起到重要作用[2,3].近年来,PPARγ配体在抑制肿瘤侵袭转移方面显示出了良好的应用前景.因此,本研究拟对PPARγ及其配体在抗肿瘤侵袭转移方面的研究作一综述.     

PPARγ激动剂的研究进展

过氧化物酶体增殖剂活化受体γ（PPARγ）是一个由配体激活的核转录因子，属于核激素受体（nuclear hormone receptor)超家族。被激动剂激活以后，该受体可以促进葡萄糖的利用以及胰岛素的增敏。因此，PPARγ激动剂有希望成为一类全新的Ⅱ型糖尿病治疗药物。本文对现有的PPARγ天然和合成的激动剂进行一个综述。     

PPARγ功能与疾病关系研究进展

过氧化物酶体增殖物激活受体γ(peroxisome prolifera-tor-activated receptor gamma(PPARγ)对脂质代谢、脂肪形成、细胞分裂和凋亡等多种生物学过程具有调节作用。近年来的研究发现,配体激活PPARγ具有抗肥胖、高血压、动脉粥样硬化、糖尿病、肿瘤等疾病的有益作用,使得围绕PPARγ受体功能和配体筛选研究成为生物医学和药理学研究的前沿热点,并有望成为治疗上述顽疾的新的药物靶标。该文就PPARγ与疾病关系的研究进展做一综述。     

PPARγ disease gene network and identification of therapeutic targets for prostate cancer

Peroxisome proliferator-activated receptor (PPAR) belongs to the nuclear hormone receptor superfamily. Recently published reports demonstrate the importance of a direct repeat 2 (DR2) as a PPARγ-responsive element in addition to the canonical direct repeat 1 (DR1) Peroxisome proliferator response elements (PPREs). However, a comprehensive and systematic approach to constructing de novo disease-specific gene networks for PPARγ is lacking, especially one that includes PPARγ target genes containing either DR1 or DR2 site within their promoter region. Here, we computationally identified 1154 PPARγ direct target genes and constructed the PPARγ disease gene network, which revealed 138 PPARγ target genes that are associated with 65 unique diseases. The network shows that PPARγ target genes are highly associated with cancer and neurological diseases. Thirty-eight PPARγ direct target genes were found to be involved in prostate cancer and two key (hub) PPARγ direct target genes, PRKCZ and PGK1, were experimentally validated to be repressed upon PPARγ activation by its natural ligand, 15d-PGJ₂ in three prostrate cancer cell lines. We proposed that PRKCZ and PGK1 could be novel therapeutic targets for prostate cancer. These investigations would not only aid in understanding the molecular mechanisms by which PPARγ regulates disease targets but would also lead to the identification of novel PPARγ gene targets.     

PPARγ overexpression regulates cholesterol metabolism in human L02 hepatocytes

Peroxisome proliferator-activator receptor (PPAR) γ is a nuclear hormone receptor that regulates glucose homeostasis, lipid metabolism, and adipocyte function. It has been shown that activation of PPARγ can reduce the incidence of gallstone. Herein we aimed to clarify the role of PPARγ in the reduction of gallstones. The plasmid containing the coding sequence of PPARγ was constructed and transfected in the human liver cell line (L02 cells). Western blot and RT-PCR were used to detect hydroxyl-methyl-glutaryl-CoA reductase (HMGCR), sterol regulatory element-binding proteins 2 (SREBP2), 7α-hydroxylase (CYP7A1), adenosine triphosphate-binding cassette (ABC) sterol transporters G5 and G8 (ABCG5, ABCG8) and liver X receptor α (LXRα). The Amplex Red cholesterol assay kit was used to detect the intracellular or extracellular cholesterol level. Our data showed that PPARγ overexpression caused significant decreases in both extracellular and intracellular cholesterol in the L02 cells. The further studies indicated PPARγ overexpression substantially decreased expression of HMGCR and SREBP-2, increased expression of CYP7A1, ABCG5, ABCG8 and LXRα. These results indicated that upregulation of PPARγ may reduce cholesterol levels through multiple-pathways including HMGCR/SREBP2-mediated biosynthesis, CYP7A1-mediated transformation, and ABCG5/ABCG8-mediated efflux. We thus suggest that PPARγ might have beneficial effects for cholesterol gallstones diseases.     

PPAR与胰岛素抵抗

PPAR即过氧化物酶体增殖物激活受体 ,是核受体超家族成员之一 ,它可以促进脂肪细胞分化 ,在脂肪代谢中起重要作用。近年来随着对胰岛素增敏剂噻唑烷二酮 (TZD)类药物作用机制的深入研究 ,发现PPARγ是该类药物的主要功能受体 ,于是展开了对于PPAR与胰岛素抵抗之间关系的研究。TZD类药物激活PPARγ ,可以改善胰岛素抵抗 ,而在基因敲除的PPARγ+ / -中 ,却发现胰岛素敏感性增加。所以 ,PPAR激活与改善胰岛素抵抗之间不是简单的正相关关系。对二者关系的进一步明确 ,对于以PPAR为靶点寻找更加有效安全的治疗Ⅱ型糖尿病药物具有关键意义     

A role of peroxisome proliferator‐activated receptor γ in non‐alcoholic fatty liver disease

Non‐alcoholic fatty liver disease is becoming a major health burden, as prevalence increases and there are no approved treatment options. Thiazolidinediones target the nuclear receptor peroxisome proliferator‐activated receptor γ (PPARγ) and have been investigated in several clinical trials for their potential in treating non‐alcoholic fatty liver disease (NAFLD) and non‐alcoholic steatohepatitis (NASH). PPARγ has specialized roles in distinct tissues and cell types, and although the primary function of PPARγ is in adipose tissue, where the highest expression levels are observed, hepatic expression levels of PPARγ are significantly increased in patients with NAFLD. Thus, NAFLD patients receiving treatment with PPARγ agonists might have a liver response apart from the one in adipose tissue. Owing to the different roles of PPARγ, new treatment strategies include development of compounds harnessing the beneficial effects of PPARγ while restricting PPARγ unwanted effects such as adipogenesis resulting in weight gain. Furthermore, dual or pan agonists targeting two or more of the PPARs have shown promising results in pre‐clinical research and some are currently proceeding to clinical trials. This MiniReview explores adipose‐ and liver‐specific actions of PPARγ, and how this knowledge may contribute in the search for new treatment modalities in NAFLD/NASH.     

Two thiophenes compounds are partial peroxisome proliferator-activated receptor α/γ dual agonists

In our previous study, two synthetic thiophenes such as IMB-05 and IMB-15 were found as peroxisome proliferator-activated receptor gamma (PPARγ) agonists and exhibited beneficial effects on glucose tolerance of diabetic mice in vivo. In the present study, their effect on the transactivity of other nuclear receptors was further investigated. IMB-05 and IMB-15 could not only activated PPARγ but also efficiently activate PPARα in GAL4-hPPARα/γ (ligand binding domain (LBD)) chimeric receptor assay and PPAR response element (PPRE)-luc reporter gene assay with EC(50) values of 1.8-5.2 μM, whereas no activity was observed in other nuclear receptor assays. In addition, the maximal efficacy of IMB-05 and IMB-15 in activating PPARα/γ was approximately 30% of that observed with Wy14643 and rosiglitazone. These data indicate that the two thiophene derivatives are novel class of partial PPARα/γ dual agonists, which may be the mechanism underlying their regulatory effects on glucose homeostasis.     

Relaxation of human pulmonary arteries by PPARγ agonists

It has been suggested that activation of nuclear peroxisome proliferator-activated receptors γ (PPARγ) may represent a new strategy for the treatment of pulmonary arterial hypertension. It has been demonstrated that PPARγ activation relaxed the isolated mouse pulmonary artery. The aims of the present study were to examine whether and to which extent the two PPARγ agonists rosiglitazone and pioglitazone relax the isolated human pulmonary artery and to investigate the underlying mechanism(s). Isolated human pulmonary arteries were obtained from patients without clinical evidence of pulmonary hypertension during resection of lung carcinoma. Vasodilatory effects of PPARγ agonists were examined on endothelium-intact or endothelium-denuded vessels preconstricted with the thromboxane prostanoid receptor agonist U-46619. Rosiglitazone and pioglitazone (0.01–100 μM) caused a concentration- and/or time-dependent full relaxation of U-46619-preconstricted vessels. The rosiglitazone-induced relaxation was attenuated by the PPARγ antagonist GW9662 1 μM, endothelium denudation, the nitric oxide synthase inhibitor L-NAME 300 μM, the cyclooxygenase inhibitor indomethacin 10 μM, and the K_ATP channel blocker glibenclamide 10 μM. The prostacyclin IP receptor antagonist RO1138452 1 μM shifted the concentration–response curve for rosiglitazone to the right. The PPARγ agonists pioglitazone and rosiglitazone relax human pulmonary arteries. The rosiglitazone-induced vasorelaxation is partially endothelium-dependent and involves PPARγ receptors, arachidonic acid degradation products, nitric oxide, and K_ATP channels. Thus, the relaxant effect of PPARγ agonists in human pulmonary arteries may represent a new therapeutic target in pulmonary arterial hypertension.