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51.
Thomas R. Vollmer Anthony Stockhausen Jin-Zhong Zhang 《The Journal of biological chemistry》2012,287(42):35212-35221
Mapracorat is a novel selective glucocorticoid receptor agonist (SEGRA), structurally distinct from corticosteroids. In preclinical studies, mapracorat potently inhibits the production of a variety of inflammatory mediators including cytokines and prostaglandin E2 (PGE2), with limited side effects associated with traditional corticosteroids. The objective of this study was to delineate the mechanisms underlying the anti-inflammatory properties of mapracorat. We found that mapracorat potently inhibited the production of GM-CSF and TNF-α in LPS-stimulated Raw 264.7 macrophages. Mapracorat also substantially attenuated the expression of COX-2 and the production of PGE2. The inhibition of mapracorat on the inflammatory response was dose-dependent, and substantially inhibitory effects were observed at concentrations in the 10–100 nm range. Examination of the activation kinetics of p38 and its downstream target MAPK-activated protein kinase-2 (MK-2) revealed a shortened activation course after LPS stimulation in cells pretreated with mapracorat. Supporting the notion that mapracorat augments a feedback control mechanism restraining the p38 pathway, we found that mapracorat enhanced the expression of MAPK phosphatase-1 (MKP-1), a critical negative regulator of MAPKs that drive the production of cytokines and other inflammatory mediators. While mapracorat alone did not stimulate MKP-1 expression, it markedly enhanced the expression of MKP-1 in cells stimulated by LPS, in a similar manner and potency to the augmenting effect of dexamethasone. Blocking MKP-1 expression by triptolide also abolished the accelerating effects of mapracorat on p38 and MK-2 deactivation, further supporting a role of MKP-1 in the anti-inflammatory mechanism of mapracorat. Taken together, these results indicate that mapracorat exerts its anti-inflammatory effects, at least in part, by augmenting MKP-1 expression. 相似文献
52.
Elizabeth J. TarlingPeter A. Edwards 《Biochimica et Biophysica Acta (BBA)/Molecular and Cell Biology of Lipids》2012,1821(3):386-395
ATP binding cassette (ABC) transporters represent a large and diverse family of proteins that transport specific substrates across a membrane. The importance of these transporters is illustrated by the finding that inactivating mutations within 17 different family members are known to lead to specific human diseases. Clinical data from humans and/or studies with mice lacking functional transporters indicate that ABCA1, ABCG1, ABCG4, ABCG5 and ABCG8 are involved in cholesterol and/or phospholipid transport. This review discusses the multiple mechanisms that control cellular sterol homeostasis, including the roles of microRNAs, nuclear and cell surface receptors and ABC transporters, with particular emphasis on recent findings that have provided insights into the role(s) of ABCG1. This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945-2010). 相似文献
53.
Maintenance of luminal NADPH in the endoplasmic reticulum promotes the survival of human neutrophil granulocytes 总被引:1,自引:0,他引:1
Kardon T Senesi S Marcolongo P Legeza B Bánhegyi G Mandl J Fulceri R Benedetti A 《FEBS letters》2008,582(13):1809-1815
The present study demonstrates the expression of hexose-6-phosphate dehydrogenase and 11 beta-hydroxysteroid dehydrogenase type 1 in human neutrophils, and the presence and activity of these enzymes in the microsomal fraction of the cells. Their concerted action together with the previously described glucose-6-phosphate transporter is responsible for cortisone-cortisol interconversion detected in human neutrophils. Furthermore, the results suggest that luminal NADPH generation by the cortisol dehydrogenase activity of 11 beta-hydroxysteroid dehydrogenase type 1 prevents neutrophil apoptosis provoked by the inhibition of the glucose-6-phosphate transporter. In conclusion, the maintenance of the luminal NADPH pool is an important antiapoptotic factor in neutrophil granulocytes. 相似文献
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《Bioorganic & medicinal chemistry letters》2014,24(11):2571-2577
We report the discovery of highly potent and selective non-steroidal glucocorticoid receptor modulators with PK properties suitable for inhalation. A high throughput screen of the AstraZeneca compound collection identified sulfonamide 3 as a potent non-steroidal glucocorticoid receptor ligand. Further optimization of this lead generated indazoles 30 and 48 that were progressed to characterization in in vivo models. X-ray crystallography was used to gain further insight into the binding mode of selected ligands. 相似文献
56.
The development of biologically active molecules based on molecular recognition is an attractive and challenging task in medicinal chemistry and the molecules that can activate/deactivate certain receptors are of great medical interest. In this contribution, selected pyrimidine/piperidine derivatives were synthesized and tested for the ability to activate/deactivate Aryl hydrocarbon receptor (AhR) and Glucocorticoid receptor (GR). Tested compounds are shown to activate the receptors but to much lesser extent than positive controls, dioxin and dexamethasone for Ahr and GR, respectively. However, some of them antagonized the positive controls action. Although further in vivo studies are needed to fully characterize the bioactivities of these compounds, the reported in vitro evidences demonstrate that they might be used as the modulators of AhR and GR activities. 相似文献
57.
Hongchao Jiao Kaifeng Zhou Jingpeng Zhao Xiaojuan Wang 《Redox report : communications in free radical research》2018,23(1):68-82
Objective: Glucocorticoids (GCs) can induce oxidative damage in skeletal muscles. The purpose of this study was to demonstrate a high caloric (HC) diet rich in soy oil would change the oxidative stress induced by a GC.Methods: The effect of dexamethasone (DEX) and HC diet on oxidative stress in plasma, skeletal muscles (M. pectoralis major, PM; M. biceps femoris, BF), and mitochondria were determined. The biomarkers of oxidative damage and antioxidative enzyme activity were determined. The fatty acid profile of muscles and the activities of complex I and II in mitochondria were measured.Results: The results showed that DEX increased the concentrations of oxidative damage markers in plasma, muscles, and mitochondria. The activity of complex I was significantly suppressed by DEX. DEX-chickens had higher proportions of polyunsaturated fatty acids and lower proportions of monounsaturated fatty acids in the PM. A HC diet decreased the levels of oxidative damage biomarkers in plasma, muscles, and mitochondria. The interaction between DEX and diet suppressed the activities of complex I and II in HC-chickens.Discussion: Oxidative damage in skeletal muscles and mitochondria was the result of GC-induced suppression of the activity of mitochondrial complex I. A HC diet improved the antioxidative capacity and reduced the oxidative damage induced by the GC. 相似文献
58.
目的:研究糖皮质激素联合吗替麦考酚酯分散片治疗系统性红斑狼疮患者的临床疗效及对免疫功能的影响。方法:选取2014年9月至2015年8月本院收治的84例系统性红斑狼疮患者,根据投硬币法分为观察组和对照组,42例每组。对照组使用单纯的糖皮质激素,观察组在此基础上使用吗替麦考酚酯分散片。比较两组患者临床疗效,治疗前后免疫球蛋白A(IgA)、免疫球蛋白(IgG)、免疫球蛋白(IgM)、C反应蛋白(CRP)、血沉(ESR)的变化及不良反应的发生情况。结果:治疗后,观察组临床总有效率显著高于对照组(P0.05)。治疗前,两组患免疫球蛋白A(IgA)、免疫球蛋白(IgG)、免疫球蛋白(IgM)、C反应蛋白(CRP)、血沉(ESR)水平比较差异均无统计学意义(P0.05);治疗后,两组患者IgA、IgG、IgM、CRP、ESR水平均较治疗前显著降低(P0.05),与对照相比,观察组的IgA、IgG、IgM、CRP、ESR明显降低(P0.05)。两组组的不良反应率比较差异无统计学意义(P0.05)。结论:糖皮质激素联合吗替麦考酚酯分散片能有效改善系统性红斑狼疮患者的免疫功能,临床疗效良好,安全性高。 相似文献
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