Effects of calcium-sensitive receptors on 11β-hydroxysteroid dehydrogenase type 2 and cortisol in neonatal mice with persistent pulmonary hypertension / 中国当代儿科杂志

OBJECTIVE@#To investigate the effects of calcium-sensitive receptors (CaSR) on the expression of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) and cortisol concentration in a neonatal mouse model of persistent pulmonary hypertension (PPH).@*METHODS@#Fifty-six newborn C57BL/6 mice were randomly divided into a control group (n=14), a PPH group (n=14), an agonist group (n=14), and an inhibitor group (n=14). The mice in the PPH, agonist, and inhibitor groups were exposed to a 12% oxygen concentration, and the agonist group and inhibitor group were given CaSR agonist (GdCl3, 16 mg/kg) and CaSR antagonist (NPS2390, 1 mg/kg) intraperitoneally once a day, respectively. The mice in control group were exposed to air, and then injected with an equal volume of normal saline as those in the PPH group every day. All mice were treated for 14 days. Morphological examination of heart and lung tissues was performed using hematoxylin-eosin staining. The expression levels of 11β-HSD2 mRNA and 11β-HSD2 protein in lung tissues were measured by qRT-PCR and Western blot respectively. Brain natriuretic peptide (BNP) and cortisol levels in lung tissues were determined using ELISA.@*RESULTS@#Compared with the control group, the PPH group had significantly increased pulmonary artery wall thickness (WT%), ratio of right to left ventricular thickness (RV/LV), alveolar mean linear intercept, and BNP concentration and a significantly reduced radial alveolar count (P<0.05); compared with the PPH group, the agonist group showed significant increases in WT% and BNP concentration, while the inhibitor group showed significant reductions in the two indicators (P<0.05). Compared with the control group, the PPH group showed significant reductions in the expression levels of 11β-HSD2 mRNA and 11β-HSD2 protein, but a significant increase in cortisol concentration (P<0.05); compared with the PPH group, the agonist group had significantly lower expression levels of 11β-HSD2 mRNA and 11β-HSD2 protein, but a significant higher cortisol concentration, while the inhibitor group showed opposite changes in these indicators (P<0.05).@*CONCLUSIONS@#CaSR may control the development and progression of PPH in newborn mice by regulating the expression of 11β-HSD2 and cortisol concentration.

Estudio e identificación de microRNA en exosomas urinarios en hipertensión arterial mineralocorticoide / Study and identification of microRNA in urinary exosomes in mineralocorticoid arterial hypertension

About 15% of the essential hypertensive patients would have a low activity of the 11ßHSD2 enzyme, which inactivates cortisol (F) to cortisone (E). Gene expression can be negatively regulated by miRNA. Urinary exosomes and their specific content (miRNA/proteins) represent a valuable tool as a biomarker for the diagnosis and prognosis of the disease. Aim: To evaluate the expression of miRNA specific for 11ßHSD2 in samples of urinary exosomes and to determine its association with biochemical variables associated with mineralocorticoid metabolism. Subjects and Methods: Cross-sectional study in subjects between 10-60 years. They were classified into subjects with high F/E (> p75) and low cortisone (< p25) and control subjects. The urinary exosomes were isolated with the Invitrogen kit. Bioinformatic analysis was performed with Mir Walk to identify specific miRNAs of HSD11B2. The expression of miRNA was evaluated by qRT PCR. The comparisons were made with the Mann-Whitney test. Results: 7.1% of the subjects are suggestive of a partial deficiency of 11ßHSD2 (NC-AME). The expression of miR-488 was higher in NC-AME than in controls (5839 ± 1719 vs 3,437 ± 2,581; p = 0.01). We found positive associations between mir-615 and ARP; miR-488 and the sodium/potassium ratio; miR-1205 with age and urinary sodium excretion; miR-494 with age, activity MMP9 and NGAL. Conclusion: We identified high expression of miR488 in NC-AME subjects and associations of miRNAs with biochemical variables associated with mineralocorticoid metabolism. Thus, exosomes and their miRNA content could be potential regulators and biomarkers of 11ßHSD2 activity.

11ß-hydroxysteroid dehydrogenase type-II activity is affected by grapefruit juice and intense muscular work

ABSTRACT Objective The enzymatic activity of 11β-hydroxysteroid dehydrogenase-2 (11β-HSD2) is key to protecting mineral corticoid receptors from cortisol and has been implicated in blood pressure regulation. Grapefruit juice (GFJ) and acidity are thought to inhibit this enzyme in vitro. This study examines the effect of GFJ and intense exercise on 11β-HSD2 enzyme activity in vivo. Subjects and methods Eighteen subjects ingested GFJ or apple juice (CON) on separate days prior to reporting to the laboratory in a randomized order. Saliva (Sal) samples were obtained at baseline, 15 and 45 minutes post-treadmill stress test; Sal cortisone (E) and cortisol (F) levels were determined, and the Sal cortisone:cortisol (E:F) ratio was used as an index of 11β-HSD2 enzyme activity at rest and after intense muscular work. Results GFJ treatment decreased baseline 11β-HSD2 enzyme activity (44%) and Sal-E (28%) compared to CON (both, p < 0.05). Sal-E (r = 0.61, p < 0.05) and Sal-F (r = 0.66, p < 0.05) were correlated with diastolic blood pressure (DBP) in GFJ-treated individuals. Treadmill stress significantly increased Sal-E and Sal-F but did not alter 11β-HSD2 enzyme activity regardless of treatment. When treatments were examined separately, CON 11β-HSD2 enzyme activity decreased by 36% (p < 0.05) from baseline to 15 post-treadmill exercise. Conclusion Our findings suggest that GFJ and intense muscular work decrease 11β-HSD-2 activity independently, and no additive effect was noted. The association between DBP and the levels of Sal-F and Sal-E during the GFJ trial should be interpreted cautiously and warrants further investigation.

Pseudohipoaldosteronismo y aparente exceso de mineralocorticoides: cara y ceca en dos pacientes pediátricos / Pseudohypoaldosteronism and apparent mineralocorticoid excess: two faces, two pediatric patients

Los síndromes endocrinológicos con hipofunción o hiperfunción con niveles paradójicos de dosajes hormonales han sido bien caracterizados en los últimos años del siglo XX, a partir del desarrollo de técnicas genéticas y moleculares. Presentamos dos pacientes con pseudohipoaldosteronismo y aparente exceso de mineralocorticoides como síndromes en espejo, con la intención de alertar al médico clínico respecto de su consideración como entidad diagnóstica en niños con alteraciones hidroelectrolíticas. (AU)

Endocrinological syndromes with underactive or overactive hormonal levels with paradoxical dosages have been well characterized over the years of the twentieth century, from the development of genetic and molecular techniques. We present two patients with pseudohypoaldosteronism and apparent mineralocorticoid excess as mirror syndromes, with the aim to alert the clinician regarding their consideration as a diagnostic entity in children with fluid and electrolyte disturbances. (AU)

11beta-hydroxysteroid dehydrogenase type 2 enzyme activity effect after exposures phthalate esters in maternal / 中华预防医学杂志

<p><b>OBJECTIVE</b>To study the association between phthalate esters (PAEs) metabolites in maternal urine and 11beta-hydroxysteroid dehydrogenase type 2 (11β-HSD2 ) enzyme activity, explore the possible mechanism of PAEs effect on fetal development.</p><p><b>METHODS</b>All of 33 cases of intrauterine growth retardation (IUGR) newborn were selected by random sampling in 2012. And 33 cases of normal control newborn were enrolled, use high performance liquid chromatography-tandem mass spectrometry method was used to detect 4 kinds of phthalate esters (PAEs) metabolites in maternal urine: mono-n-butyl phthalate ester (MBP), mono (2-ethylhexyl) phthalate (MEHP), mono (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono (2-ethyl-5-oxohexyl) phthalate (MEOHP) and three kinds of cortisol corticosterone metabolites, tetrahydrocortisol (THF), allo-tetrahydrocortisol (allo-THF), tetrahydrocortisone (THE), and analyze the association between phthalate esters (PAEs) metabolites in maternal urine and 11β-HSD2 enzyme activity.</p><p><b>RESULTS</b>MBP, MEHP, MEHHP, MEOHP metabolites can be detected in 98% (65 cases) , 89% (59 cases), 91% (60 cases), 91% (60 cases) of all 66 maternal urine samples, respectively. The median concentrations of test material in case group were 31.20 ng/ml for MBP, 24.61 ng/ml for MEHHP, 11.72 ng/ml for MEOHP and 48.67 ng/ml for SumDEHP which were significantly higher than those of the control group (were 17.32, 12.03, 5.68 and 28.64 ng/ml); 11β-HSD2 activity in case group ((THF+allo-THF)/THE = (0.79 ± 0.09) ng/ml) was significantly lower than that of the control group((THF+allo-THF)/THE = (0.58 ± 0.04) ng/ml); PAEs metabolites MBP (β' = 1.12), MEHHP(β' = 1.14), MEOHP(β' = 1.10), SumDEHP(β' = 1.08) in baby boy mother's urine was reversely correlated to 11β-HSD2 activity.</p><p><b>CONCLUSIONS</b>PAEs could affect fetal development by inhibit 11β-HSD2 activity.</p>

Association between HSD11B2 gene polymorphism and fetal growth / 南方医科大学学报

<p><b>OBJECTIVE</b>To explore the relationship between HSD11B2 polymorphisms and fetal growth during normal pregnancy.</p><p><b>METHODS</b>The HSD11B2 promoter/G-209A, G-194C, G-151A and G-126A genotypes were examined in 33 samples from Chinese Han subjects by gene sequencing. HSD11B2 (CA)n microsatellite polymorphism in the first intron was detected in blood samples from 187 maternal and newborn pairs by PCR-capillary electrophoresis.</p><p><b>RESULTS</b>All the HSD11B2 promoter/G-209A, G-194C, G-151A and G-126A genotypes were wild-type GG. The offspring birth weight and any ultrasound parameters describing late gestational fetal body shape were not significantly different between maternal or fetal SS, SL and LL groups or combined SS+SL and LL groups. When considering the relevant confounding factors (gestational age at delivery, newborn's gender, maternal body mass index before pregnancy, maternal weight at delivery and maternal age), the offspring birth weight and late pregnancy ultrasound parameters were still not associated with the maternal or fetal HSD11B2 (CA) n microsatellite polymorphisms.</p><p><b>CONCLUSIONS</b>Fetal and maternal HSD11B2 polymorphism is not related to fetal growth during normal pregnancy.</p>

Roles of type II 11β-hydroxysteroid dehydrogenase and its signaling factors in pathogenesis of persistent pulmonary hypertension in neonatal rats / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To study the roles of type II 11β-hydroxysteroid dehydrogenase (11β-HSD2) and it's signaling factors in the lung tissue in pathogenesis of persistent pulmonary hypertension (PPH) in neonatal rats.</p><p><b>METHODS</b>Six Sprague-Dawley rats on the 19th day of pregnancy were randomly divided into PPH and control groups (n=3 each). The PPH group was intraperitoneally injected with indomethacin (0.5 mg/kg) twice daily and exposed in 12% oxygen for three days, in order to prepare a fetal rat model of PPH. The control group was intraperitoneally injected with an equal volume of normal saline and exposed to air. Neonatal rats were born by caesarean section from both groups on the 22nd day of pregnancy. In each group, 15 neonatal rats were randomly selected and sacrificed. 11β-HSD2 expression in the lung tissue of neonatal rats were observed by Confocal laser technology, and serum cortisol levels and prostacyclin, renin, angiotensin and aldosterone in the lung tissue of both groups were measured using ELISA.</p><p><b>RESULTS</b>11β-HSD2 protein was widely expressed in the lung tissue of the control and PPH groups. The levels of 11β-HSD2 and prostacyclin in the lung tissue were lower in the PPH group than in the control group, while serum cortisol levels and renin, angiotensin and aldosterone in the lung tissue were higher in the PPH group than in the control group (P<0.05).</p><p><b>CONCLUSIONS</b>11β-HSD2 and it's signaling factors play roles in pathogenesis of PPH in neonatal rats.</p>

Terpenoids and sterols from Ricinus communis and their activities against diabetes / 中国中药杂志

Seven terpenoids and three sterols were isolated from the methanol extracts of the aerial parts of Ricinus communis by chromatography methods and their structures were identified by spectra analysis as ficusic acid( 1), phytol(2), callyspinol(3) , lupeol(4), 30-norlupan-3beta-ol-20-one(5) , lup-20(29)-en-3beta,15alpha-diol(6) , acetylaleuritolic acid( 7), stigmast4-en-3-one(8) , stig-mast-4-en-6beta-ol-3-one(9) , and stigmast4-en-3,6-dione(10). Compounds 1-3 and 5-10 were obtained from this species for the first time and 5 and 6 showed significant inhibitive activity and good selectivity against 11beta-HSD of mouse and human in vitro. [Key words] Ricinus communis; terpenoids; sterols; 11beta-HSD

Expression of 11β-hydroxysteroid dehydrogenase type 2 in lymphoblastic cells and its relationship with glucocorticoid sensitivity / 中国实验血液学杂志

This study was aimed to explore the expression of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) in 3 different lymphoblastic cell lines with relation to their glucocorticoid (GC) sensitivity. The 11β-HSD2 expressions in acute lymphoblastic leukemia Jurkat cells, lymphoma Daudi and Raji cells, and peripheral blood T cells of a healthy volunteer were analyzed by real time PCR and Western blot. Glucocorticoid (GC)-induced apoptosis in 3 different cell lines was detected by flow cytometry. Cell growth in Jurkat cells treated with cortisol was analyzed by trypan blue dye exclusion. Flow cytometry was performed to observe GC-induced apoptosis in Jurkat cells treated by combination of GC with 11β-HSD2 inhibition 18β-glycyrrhetinic acid (18β-GA). The results demonstrated that 11β-HSD2 highly expressed in Jurkat cells, but not in Daudi, Raji cells and normal blood T cells. Compared to Daudi and Raji cells, Jurkat cells were more resistant to GC-induced apoptosis. Furthermore, the inhibition of 11β-HSD2 by 18β-GA resulted in increased cellular sensitivity to GC as shown by elevated induction of apoptosis. it is concluded that 11β-HSD2 is at least partly responsible for GC resistance in Jurkat cells. 11β-HSD2 may be a potential target for reduction of GC-resistance in therapeutic applications.

Atrial 11beta-hydroxysteroid dehydrogenase type 2 expression in rheumatic heart disease patients with or without atrial fibrillation / 中华心血管病杂志

<p><b>OBJECTIVE</b>To investigate the mRNA and protein expressions of 11beta-Hydroxysteroid dehydrogenase type 2 (11betaHSD2) in patients with atrial fibrillation.</p><p><b>METHODS</b>Right and left atrial lateral wall tissue samples were obtained during mitral/aortic valve replacement operation from 25 patients with rheumatic heart valve disease (12 in sinus rhythm and 13 in chronic atrial fibrillation). Realtime quantitative PCR and Western blot were used to determine the mRNA and protein expressions of 11betaHSD2 in atria specimens. The distribution of 11betaHSD2 in human atrial tissue was analyzed by specific immunohistochemical staining. Echocardiography examination was performed before operation.</p><p><b>RESULTS</b>The left atrial diameters were significantly higher in the atrial fibrillation group as compared to sinus rhythm group (P < 0.01). Similarly, mRNA expression of 11betaHSD2 (0.86 +/- 0.14 vs 0.33 +/- 0.12 in right atria, 0.95 +/- 0.15 vs 0.37 +/- 0.10 in left atria, all P < 0.01) and protein expression of 11betaHSD2 (1.18 +/- 0.64 vs 0.71 +/- 0.21 in right atria, P < 0.01; and 1.36 +/- 0.58 vs 0.85 +/- 0.15 in left atria, P < 0.05) were also significantly upregulated in atrial fibrillation groups than those in sinus rhythm groups. The mRNA and protein expressions of 11betaHSD2 were similar between left atria and right atria both in fibrillation and sinus groups (all P > 0.05). The special immunohistochemical staining demonstrated that 11betaHSD2 was abundant in the human atrial myocardium and located mainly in the cytoplasm.</p><p><b>CONCLUSION</b>These findings suggested that upregulated 11betaHSD2 might be associated to the development and persistence of atrial fibrillation.</p>