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l 0.5 CMC; prednisone acetate 100 mg?kg 1; prednisone acetate plus emodin ; prednisone acetate Celecoxib plus emodin ; dexamethasone ; and dexamethasone plus emodin . Prednisone or dexamethasone was administered by oral gavage twice day-to-day to induce a state of glucocorticoid excess and insulin resistance in mice. Emodin was administered orally twice day-to-day 1 day just before, after which at the same time as prednisone or dexamethasone. Following 14 days of treatment, insulin tolerance was determined in mice deprived of food overnight to investigate the effect of emodin on prednisone or dexamethasoneinduced insulin resistance. Effect of emodin in DIO mice C57BL 6J male mice had been fed a formulated analysis diet program containing 60 with the calories from fat for 12 weeks just before, and throughout the duration with the experiment.
DIO mice had been assigned to three groups and subjected to gavage treatment twice per day with vehicle , emodin 50 or 100 mg?kg 1, respectively, for 35 days. Fasting blood glucose values and initial body weights had been comparable in between groups. The blood glucose levels had been measured via blood drops obtained by clipping the tail with the mice utilizing a One TOUCH Fundamental plus Glucose Celecoxib Monitor , unless otherwise specified. The food intake and body weight with the animals had been recorded each 3 days. Glucose tolerance test was determined in mice deprived of food for 5 h at day 24 with the treatment. The blood samples had been collected via the retroorbital sinus, along with the serum glucose and insulin concentrations had been measured with an enzymatic colorimetric system and insulin ELISA kit, respectively.
An insulin tolerance test was performed within the 5 h fasted mice at day 28 with the treatment. On the last day of treatment, 5 h fasted Alogliptin mice had been anaesthetized with an i.p. injection of sodium pentobarbital . Serum was collected for determination of insulin, triacylglycerol, cholesterols and non esterified free fatty acid concentration. The liver and diverse fat pads which includes epididymal fat, mesenteric fat, perirenal fat and subcutaneous fat had been dissected, weighed, instantly frozen in liquid nitrogen and stored at 80 C. Emodin and other compounds had been purchased from Nanjing Zelang Medical Technology Co. Ltd The pcDNA expression vector and Trizol Reagent had been purchased from Invitrogen . cortisone was from Amersham . cortisol was from PerkinElmer . SPA beads had been from GE . Super Block Blocking Buffer was from Pierce .
The murine monoclonal cortisol antibody was from East Coast Biologics . Glycyrrhetinic acid was from Sigma . The M MLV reverse transcriptional enzyme was from Promega . All of the primers had been synthesized by Sangon Corporation . SYBR Green Supermix was from Bio Rad. The high fat forage was from Research Diet plan . Blood glucose values had been measured utilizing a One Touch Fundamental Glucose HSP Monitor . Serum insulin was analysed with a mice insulin ELISA kit . Serum NEFA was determined with an enzymatic colorimetirc system utilizing oleic acid as a standard . Serum triacylglycerols and cholesterols had been analysed with an enzymatic colorimetric system . The potency and selectivity of a series anthraquinone compounds on the inhibition of mouse or human 11b HSD1 or 2 had been determined by SPA.
IC50 values are presented in Table 1. Emodin, aloe emodin and rheochrysidin showed a robust inhibitory effect on recombinant mouse 11b HSD1 with IC50 of 86, 98 and 81 nM, respectively. Alogliptin Emodin also inhibited human 11b HSD1 with IC50 of 186 nM, whereas aloe emodin and rheochrysidin had been much less potent using the IC50 of 879 and 542 nM, respectively. The other two anthraquinone compounds, rhein and 3 methylchrysazin, exhibited substantially weaker inhibitory effects on both mouse and human 11b HSD1. All of the five anthraquinone compounds showed good selectivity for mouse 11b HSD2 with an IC50 ??1 mM, and emodin did not have a substantial inhibitory effect on human 11b HSD2. Thus, a series anthraquinone compounds had been identified as selective 11b HSD1 inhibitors, emodin becoming essentially the most potent.
Molecular modelling of emodin and 11b HSD1 To explain the interaction mode of emodin to human 11b HSD1, molecular docking simulation was performed employing the plan DOCK4.0 according to the X ray crystal structure with the 11b HSD1 complex . This complex structure is composed of human 11b Celecoxib HSD1, a synthetic inhibitor with high activity, and a co substrate nicotinamide adenine dinucleotide phosphate . The emodin was docked into the binding website flexibly; meanwhile, the structure of 11b HSD1 and NADP was fixed. The conformation using the lowest interaction energy was taken out for further analysis. In the initial crystal structure, hydrogen bonds supply robust interactions in between the ligand along with the protein, as well as its co substrate NADP. The carbonyl group with the ligand forms two hydrogen bonds with Tyr183 and Ser170. Interestingly, the docking results showed that emodin also formed robust hydrogen bonds using the Alogliptin receptor, as shown in Figure 1. The hydroxyl on C4 formed hydrogen bonds with Ser170, and the