کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10848010 | 1070522 | 2013 | 10 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Identification of 15d-PGJ2 as an antagonist of farnesoid X receptor: Molecular modeling with biological evaluation
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کلمات کلیدی
FXREPLA2CDCAHTRFBSEPRUSFXRPGH215-Deoxy-Δ12,14-PGJ2PPARα6α-ethyl-chenodeoxycholic acidPPARγiNOSAF-2PGD215d-PGJ2DTTcholesterol 7a-hydroxylaseDMEMFBSkoffCYP7A1Retinoid X Receptor αRXRα6-ECDCALBDGuggulsteroneLXRIPTGIC5050% inhibitory concentration - 50٪ غلظت مهاریkeap1 - buy1DMSO - DMSOfarnesoid X receptor - Farnesoid X گیرندهinducible NO synthase - NO سنتاز القاء شدهROS - ROSAntagonist - آنتاگونیستChenodeoxycholic acid - اسید ChenodeoxycholicArachidonic acid - اسید آراشیدونیکisopropyl β-d-thiogalactoside - ایزوپروپیل β-d-thiogalactosideSurface plasmon resonance - تشدید پلاسمون سطحیSPR - تشدید پلاسمون سطحیtumor necrosis factor α - تومور نکروز عامل αFluorescence quenching - خنک شدن فلورسنتligand binding domain - دامنه اتصال لیگاندMolecular dynamics - دینامیک ملکولی یا پویایی مولکولیDimethyl sulfoxide - دیمتیل سولفواکسیدrosiglitazone - روزیگلیتازونfetal bovine serum - سرم جنین گاوMolecular dynamics simulation - شبیه سازی دینامیک مولکولیTNF-α - فاکتور نکروز توموری آلفاDulbecco’s modified eagle’s medium - محیط عقاب اصلاح شده Dulbeccokon - می تواندresponse units - واحدهای پاسخKelch-like ECH-associated protein 1 - پروتئین مرتبط با ECH کلچ 1Prostaglandin D2 - پروستاگلاندین D2Prostaglandin H2 - پروستاگلاندین H2liver X receptor - کبد X گیرندهextracellular signal-regulated kinase - کیناز تنظیم شده سیگنال خارج سلولیperoxisome proliferator-activated receptor γ - گیرنده پروتئین کننده پروکسیوم فعال γNuclear receptor - گیرنده هستهای، گیرندههای هستهای
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
زیست شیمی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
15-Deoxy-Î12,14-PGJ2 (15d-PGJ2) is one of the major metabolites from prostaglandin D2 in arachidonic acid (AA) metabolic pathway. It was determined as a ligand of peroxisome proliferator-activated receptor γ (PPARγ) functioning potently in adipocyte development. However, the fact that 15d-PGJ2 exerts also PPARγ-independent biological actions has highly addressed its multi-target behavior. Here, we identified that 15d-PGJ2 was an antagonist of farnesoid X receptor (FXR), as investigated by surface plasmon resonance, fluorescence quenching and homo time-resolved fluorescence based analyses, and the coactivator-recruitment and luciferase-reporter related investigation. Assay of 15d-PGJ2 regulation on hFXRα target genes revealed that treatment of HepG2 cells with 15d-PGJ2 resulted in the stimulation of mRNA expressions of bile-salt export pump (BSEP), and the decrease of cholesterol 7a-hydroxylase (CYP7a1). In addition, functional assays indicated that 15d-PGJ2 promoted the conversion of cholesterol to bile acids in HepG2 cells. Moreover, molecular docking combined with molecular dynamics simulation was applied to develop the possible model of 15d-PGJ2 binding to hFXRα ligand binding domain (LBD) at atomic level, and the responsible residues for 15d-PGJ2/hFXRα-LBD interaction were thereby determined, which were further confirmed by SPR assays against hFXRα-LBD site-directed mutations. Given that hFXRα functions potently in the regulation of hepatic bile acid metabolism and lipid/glucose homeostasis, our current work is expected to help better understand the multi-target features of this PGD2 metabolite in biological pathways, and 15d-PGJ2 as a new discovered FXR antagonist might find its potential application in further anti-hypercholesterol research.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Steroids - Volume 78, Issue 9, September 2013, Pages 813-822
Journal: Steroids - Volume 78, Issue 9, September 2013, Pages 813-822
نویسندگان
Xing Xu, Yin Lu, Lili Chen, Jing Chen, Xiaomin Luo, Xu Shen,