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Objective:The 11?-hydroxysteroid dehydrogenase(11?-HSD) plays an important role in tumor biological behavior,and the 11?-HSD inhibitor Glycyrrhetinic acid(GA) may have an anticancer effect,although its mechanism remains unkown.This study aimed to observe the expressions of 11?-HSD 1 and 2 in colorectal cancer and the effects of glucocorticoid and GA on colorectal cancer cells.Methods: The mRNA expressions of 11?-HSD1 and 2 in the human colorectal cancer cell line HCT-8 were detected by reverse transcription polymerase chainreaction(RT-PCR),and the protein expressions of 11?-HSD1 and 2 were detected by Western blot.The inhibition of the growth of the HCT-8 cells was determined by MTT assay after treated with glucocorticoid,cosubstrate,GA only or their combination.Results: The expression of 11?-HSD2 mRNA and proteins but not that of 11?-HSD1 mRNA and proteins was expressed in the HCT-8 cells.The rate of cell growth inhibition was(40.87 ? 1.47)% after a 12-hour treatment with cortisol,and it was(5.79 ? 0.20)% in the cortisol + NAD group,with statistically significant difference(P
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Objective To investigate effects of endotoxin on 11?-HSD2 gene transcription in vascular endothelial cells to observe the role of p38 mitogen-activated protein kinase (p38 MAPK) signaling pathway. Methods The effects of endotoxin in the presence or absence of p38 MAPK specific inhibitor SB203580 on the transcription of 11?-HSD2 in vascular endothelial cells was evaluated by reverse transcription DNA polymerase chain reaction. Results Treatments of endotoxin (1.0, 10, 20, 50, 100 ?g/ L) for 24 h increased the ratios of 11?-HSD2mRNA/?-actin mRNA in vascular endothelial cells. The induction of 11?-HSD2 mRNA by endotoxin could be inhibited partially by 10 mmol/ L SB203580. Conclusion Endotoxin stimulated the transcription of 11?-HSD2 gene in vascular endothelial cells. The activation of p38 MAPK might be an important mechanism of 11?-HSD2 gene induced by endotoxin.
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Intraperitoneal glucose tolerance test was performed in the streptozotocin- and high fat-induced diabetic rats and normal rats.The results of RT-PCR and Western blot showed that the expression of 11?- hydroxysleroid dehydrogenase type 1 (11?-HSD1) was higher in the diabetic rats than that in control and was correlated with fasting plasma glucose,insulin and AUC-I/G with respective correlation coefficient (r) of 0.870, - 0.799,- 0.850,suggesting that increased expression of 11?-HSD1 appears to damage?-cell function through magnifying the local effect of glucocorticoids.
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Objective:To observe the effect of thyroid hormones on 11?-hydroxysteroid dehydrogenase type 1(11?-HSD1) in newborn rats' hippocampus. Methods: Hypothyroid model was induced with propylthiouracil(PTU, 50 mg/d) in SD rats in the last week of pregnancy and was confirmed by measuring the levels of thyroid hormones and thyrotropin(TSH) in the newborn rats' blood. Western blot was used to determine the expression of 11?-HSD1 in hippocampus in newborn rats. Effects of triiodothyronine(T 3) and synthetic glucocorticoid dexamethasone(Dex) on expression of 11?-HSD1 in primarily- cultured hippocampus were studied with thin layer chromatography(TLC) and Western blot. Results: Thyroid hormone levels decreased and TSH level increased in the newborn rats' blood. The expression of 11?-HSD1 decreased by 41.6% in the hippocampus of newborn rats born to the mothers treated with PTU. T 3(10 -9 ,10 -8 ,10 -7 mol/L) and Dex(10 -7 mol/L) up-regulated the activity of 11?-HSD1 by 29.4%,45.6%,60.9% and 39.8%,respectively. T 3(10 -9 ,10 -8 ,10 -7 mol/L) and Dex(10 -7 mol/L) increased the expression of 11?-HSD1 protein by 26.0%,43.2%,64.9% and 41.1%,respectively.Synergistic effect of T 3 and DEX was observed in terms of regulating 11?-HSD1: the expression of 11?-HSD1 increased by 123.3% in the hippocampal neurons exposed to both Dex(10 -7 mol/L) and T 3 (10 -7 mol/L) and the activity increased by 114.1%. Conclusion:Thyroid hormone can up-regulate the expression of 11?-HSD1 in the hippocampus during brain maturation either by itself or synergistically with glucocorticoid, thereby enhancing the action of glucocorticoids on the brain.
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4-fold elevation in renal cortex in plasma aldosterone as compared to those of the SHAM rats. The above pathologies were markedly improved in bi-ectomised rats with significantly lower aldosterone level. Being constantly infused exogenous aldosterone, bi-ectomized rats manifested greater proteinuria, hypertension, glomerulosclerosis and increased level of TGF-?1 compared to bi-ectomised rats. Indeed, these features were similar in exogenous aldosterone rats and 5/6 nephrectomized rats. Furthermore, the expression of mineralocorticoid receptor (MR) mRNA was remarkablely enhanced in SNX group and was decreased in ADX group. However, the mRNA expression of 11 ?-hydroxysteroid dehydrogenase II (11?-HSD2) in each group was opposite to that of MRmRNA. Ccr and kidney/body weight showed no differences among four experimental groups. Conclusion Aldosterone contributes to the progression of ablative nephropathy in the rat through mechanisms other than systolic blood pressure.
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Objective:To study the toxicity of 11 dehydrocorticosterone on hippocampal neurons and to determine whether 11? hydroxysteroid dehydrogenase (11? HSD1) is involved in the neurotoxity. Methods:Western blotting, radiometric enzyme activity assay and MTT assay were employed in this study. Results:Both 11? HSD1 protein and bioactivity were positive in the hippocampal neurons as demonstrated by Western blotting and radiometric enzyme activity assay. At concentration of 10 -6 mol/L, 11 dehydrocorticosterone was neurontoxic to hippocampal neurons cultured in serum free DMEM medium. This neurotoxic effect of 11 dehydrocorticosterone was blocked by 11? HSD1 inhibitor carbenoxolone (CBX) and glucocorticoid receptor (GR) antagonist RU38486, but not by mineralcocorticoid receptor (MR) antagonist spironolatone. Corticosterone and its derivative 11 dehydrocorticosterone up regulated 11? HSD1 level. Conclusion:11 dehydrocorticosterone has toxicity on hippocampal neurons, and it can be blocked by CBX, suggesting 11? HSD1 may convert biologically inactive 11 dehydrocorticosterone to active corticosterone. The up regulation of 11? HSD1 by glucocorticoids in return exaggerates the neurotoxic effect of corticosterone, which may play a positive role in the delayed neuron death during stress.
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Objective:To observe the imprinting effects of prenatal overexposure to glucocorticoids on 11?-hydroxysteroid dehydrogenase type 1(11?-HSD1) expression in the rat offspring liver. Methods: Pregnancy was determined by examining vaginal smear. Eight pregnant rats were divided into dexamethasone(DEX) group and normal saline(NS) group at random with each group containing 4 rats.DEX group was given subcutaneous injection of DEX [0.05 mg/(kg?d)] and NS group was given injection of NS.Western blot was adopted to determine 11?-HSD1 protein in the liver of the offspring at the age of 4 months;RT-PCR was used to determine 11?-HSD1 mRNA and hepatic phosphoenolpyruvate carboxykinase(PEPCK) mRNA;and glucose oxidase method was used to measure the blood glucose concentration. Results: Western blot and RT-PCR showed that prenatal overexposure to DEX increased the expression of 11?-HSD1 protein and mRNA in the liver of the female offsprings at 4 months old, but not in male offsprings.Prenatal overexposure to DEX also increased the expression of PEPCK mRNA and blood glucose level in the female offsprings at 4 months old.Conclusion:Our study suggests that prenatal overexposure to glucocorticoids throughout gestation can imprint the expression of 11?-HSD1 in rat offsprings liver, which may lead to the PEPCK overexpression and blood glucose elevation.Development of diabetes may be induced in individuals overexposed to glucocorticoids during fetal period.