11beta-hydroxysteroid Dehydrogenase Type Research Articles

Design, synthesis, molecular docking and in vitro evaluation of benzothiazole derivatives as 11β-hydroxysteroid dehydrogenase type 1 inhibitors

11-Beta hydroxysteroid dehydrogenase type 1 (11β-HSD1) regulates cortisol levels mainly in adipose, hepatic and brain tissues. There is a relationship between the high activity of this enzyme and the development of obesity and metabolic disorders. The inhibition of 11β-HSD1 has been shown to attenuate the development of type 2 diabetes mellitus, insulin resistance, metabolic syndrome and other diseases mediated by excessive cortisol production. In this work, fifteen benzothiazole derivatives substituted with electron-withdrawing and electron-donating groups were designed to explore their affinity for 11β-HSD1 using in silico methods. The results show that (E)-5-((benzo[d]thiazol-2-ylimino)(methylthio)methylamino)-2-hydroxybenzoic acid (C1) has good physicochemical properties and favorable interactions with 11β-HSD1 through hydrogen bonding and hydrophobic interactions in the catalytic site formed by Y183, S170 and Y177. Furthermore, C1 was synthesized and evaluated in vitro and ex vivo using clobenzorex (CLX) as a reference drug in obese Zucker rats. The in vitro results showed that C1 was a better inhibitor of human 11β-HSD1 than CLX. The ex vivo assay results demonstrated that C1 was capable of reducing 11β-HSD1 overexpression in mesenteric adipose tissue. Therefore, C1 was able to decrease the activity and expression of 11β-HSD1 better than CLX.

Interaction of HSD11B1 and H6PD polymorphisms in subjects with type 2 diabetes are protective factors against obesity: a cross-sectional study

BackgroundThe enzyme 11-beta hydroxysteroid dehydrogenase type 1 (HSD11B1) converts inactive cortisone to active cortisol in a process mediated by the enzyme hexose-6-phosphate dehydrogenase (H6PD). The generation of cortisol from this reaction may increase intra-abdominal cortisol levels and contribute to the physiopathogenesis of obesity and metabolic syndrome (MetS). The relationship of HSD11B1 rs45487298 and H6PD rs6688832 polymorphisms with obesity and MetS was studied. We also studied how HSD11B1 abdominal subcutaneous (SAT) and visceral adipose tissue (VAT) gene expression is related to body fat distribution.MethodsRates of obesity and MetS features were cross-sectionally analyzed according to these polymorphisms in 1006 Brazilian white patients with type 2 diabetes (T2DM). Additionally, HSD11B1 expression was analyzed in VAT and SAT in a different cohort of 28 participants with and without obesity who underwent elective abdominal operations.ResultsAlthough polymorphisms of the two genes were not individually associated with MetS features, a synergistic effect was observed between both. Carriers of at least three minor alleles exhibited lower BMI compared to those with two or fewer minor alleles adjusting for gender and age (27.4 ± 4.9 vs. 29.3 ± 5.3 kg/m2; P = 0.005; mean ± SD). Obesity frequency was also lower in the first group (24.4% vs. 41.6%, OR = 0.43, 95% CI 0.21–0.87; P = 0.019). In the second cohort of 28 subjects, HSD11B1 gene expression in VAT was inversely correlated with BMI (r = − 0.435, P = 0.034), waist circumference (r = − 0.584, P = 0.003) and waist-to-height ratio (r = − 0.526, P = 0.010).ConclusionsThese polymorphisms might interact in the protection against obesity in T2DM individuals. Obese individuals may have decreased intra-abdominal VAT HSD11B1 gene expression resulting in decreasing intra-abdominal cortisol levels as a compensatory mechanism against central and general adiposity.

Licorice: From Pseudohyperaldosteronism to Therapeutic Uses.

Licorice has been used as a medicinal plant from 2.500 years. It shows a wide range of biological and pharmacological activities, including anti-inflammatory and immune regulatory actions. One of its most known effects is the induction of hypertension, and it can induce what appears to be pseudohyperaldosteronism, due to glycyrrhetinic acid, the main active component of the root. Glycyrrhetinic acid and metabolites block the 11 beta-hydroxysteroid dehydrogenase type 2 and also bind mineralocorticoid receptors directly, acting as agonists. However, other interesting therapeutic uses of licorice are linked to its anti-androgen and estrogen-like activity, especially in the treatment of polycystic ovary syndrome (PCOS) in conjunction with spironolactone therapy. In this brief review, we report the main features and possible therapeutic uses of this ancient plant.

Potential role of microRNA-424 in regulating ERRγ to suppress trophoblast proliferation and invasion in fetal growth restriction

BackgroundAbnormal expression of estrogen-related receptor γ (ERRγ) protein is associated with fetal growth restriction (FGR). The upstream regulators of ERRγ are still unknown. ObjectiveTo evaluate the placental expression level of microRNA-424 (miR-424) and to demonstrate the relationship between miR-424 and FGR. MethodsThe expression levels of miR-424 were detected in FGR and control placentas. HTR-8/SVneo cells were transfected with mimics or inhibitors to increase or decrease the miR-424 expression level, respectively. The transwell and CCK-8 assays were used to determine trophoblast-derived cell line invasion and proliferation. The expression levels of miR-424, ERRγ, and 17 beta-hydroxysteroid dehydrogenase type 1 (HSD17B1) were detected by qRT-PCR and Western blotting. The relationship between miR-424, ERRγ, and HSD17B1 was determined by luciferase reporter assay. ResultsCompared to the normal pregnancy group, FGR placental tissues showed a significantly higher expression level of miR-424. The up-regulation of miR-424 decreased trophoblast-derived cell line invasion and proliferation. Down-regulation of miR-424 enhanced invasive and proliferative abilities of the cell lines. Over-expression of miR-424 reduced ERRγ protein levels and decreased both mRNA and protein levels of HSD17B1. Thus down-regulation of miR-424 induced protein expression of ERRγ and enhanced the mRNA and protein expressions of HSD17B1. MiR-424 probably mediated the expression of ERRγ via binding to sites other than mRNA 3′UTR. ConclusionMiR-424 may be associated with the pathogenesis of FGR by modulating trophoblast-derived cell line proliferation and invasion. MiR-424 may play a role in mediating the protein expressions of ERRγ and HSD17B1.

MON-447 Impact Of Cortisone And Glucocorticoid Metabolites On Bone Turnover Markers in Male Patients With Hypopituitarism

Background: Glucocorticoid therapy is the most common cause of iatrogenic osteoporosis. Less is known on the effect of glucocorticoids on bone remodeling when used as replacement therapy in patients with adrenal insufficiency. Enhanced intracellular conversion of cortisone to active cortisol, by 11beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and other enzymes leading to alterations in glucocorticoid metabolism may contribute to a deleterious effect on bone health in this patient group. Study Design: An open crossover prospective study randomizing ten hypopituitary men, with severe ACTH deficiency, to three commonly used hydrocortisone dose regimens. Measurements: Following 6 weeks of each regimen, patients underwent 24-hour serum cortisol/cortisone sampling, measurement of bone turnover markers, and a 24-hour urine collection for measurement of urinary corticosteroid metabolites by GC-MS. Serum cortisone and cortisol were analysed by LC-MS/MS. Results: Dose related and circadian variations in serum cortisone were seen to parallel those for cortisol. The median area under the curve (AUC) of serum cortisone was significantly higher in patients on dose A (20mg/10mg) [670.5 (IQR 621-809.2)] compared to those on dose C (10mg/5mg) [562.8 (IQR 520.1-619.6), p=0.01]. A negative correlation was observed between serum cortisone and bone formation markers, OC[1-49] (r=-0.42, p=0.03), and PINP (r=-0.49, p=0.01). There was a negative correlation between the AUC of night-time serum cortisone levels with the bone formation marker, OC[1-49] (r= -0.41, p=0.03) but there were no significant correlations between day-time serum cortisone or cortisol with bone turnover markers. There was a negative correlation between total urinary cortisol metabolites and the bone formation markers, PINP (r=-0.39, p=0.04), and OC[1-49] (r=-0.35, p=0.06). Conclusion: Serum cortisone and total urinary total cortisol metabolites are associated with alterations in bone turnover markers suggesting an important role of tissue-specific metabolism of glucocorticoids on bone metabolism in patients receiving HC replacement therapy.

SUN-112 Arcuate 11-Betahydroxysteroid Dehydrogenase Type1 Regulates Energy Homeostasis

Introduction: Despite the ongoing increase in the prevalence of obesity, there are few licensed anti-obesity medications, and these therapies have limited efficacy and significant side effects. Therefore, new treatments are being developed, including 11-βhydroxysteroid dehydrogenase type1 (11βHSD1) inhibitors. In vivo, the enzyme 11-βhydroxysteroid dehydrogenase type1 (11βHSD1), converts the inactive glucocorticoid, 11-dehydrocorticosterone, to its active form (corticosterone). Tissue-specific 11βHSD1 has been reported to be important in the development of obesity. 11βHSD1 is expressed in the arcuate nucleus (ARC), a major hypothalamic centre which regulates energy homeostasis. We investigated the effect of modulation of intra-ARC 11βHSD1 expression on appetite and body weight in rodents. Methods: Experiments were performed using adult male Wistar rats fed a standard chow diet. In the overexpression experiment, recombinant adeno-associated virus (rAAV) encoding 11βHSD1 (rAAV-S11βHSD1) was injected bilaterally into the ARC of 12 rats and rAAV expressing green fluorescent protein (rAAV-GFP) was injected bilaterally into the ARC of 12 control rats. In the underexpression experiment, rAAV encoding small interfering RNA to 11βHSD1 (rAAV-si11βHSD1) was injected bilaterally into the ARC of 12 rats and rAAV-GFP injected into the ARC of 12 control rats. Starting 1 week post-surgery, body weight and food intake were measured three times a week for 10 weeks. At the end of the experiments, tissues and plasma were collected for gene expression and hormone analysis. Results and Conclusions: Compared to controls, ARC 11βHSD1 overexpression increased ARC corticosterone levels (iARC-S11βHSD1 243±34pg/mg vs iARC-GFP 89±39pg/mg, p<0.05), resulting in hyperphagia and 6% greater weight gain. ARC 11βHSD1 underexpression decreased ARC corticosterone levels by 47% (iARC-si11βHSD1 124.9±14.59pg/mg vs iARC-GFP 262.1±47.3pg/mg, p=0.01), resulting in 5% lower weight gain and a 1.7-fold increase in interscapular brown adipose tissue uncoupling protein-1 expression compared to controls. Corticosterone levels were unchanged in the neighbouring paraventricular nucleus. Additonally, systemic ACTH and corticosterone were unaffected by altered ARC 11βHSD1 expression. Our results suggest ARC 11βHSD1 plays a significant role in the regulation of energy homeostasis. Therefore, the novel class of therapies, 11βHSD1 inhibitors, may require central activity for maximal anti-obesity efficacy. Sources of Support: MRC MR/M004171/1, NIHR RP-2014-05-001, BBSRC BB/E52708X, FP7- HEALTH- 2009- 241592 EuroCHIP Grant

SAT-023 Cyclic Regulation of 11 Beta-Hydroxysteroid Dehydrogenase Type 1 in Endometriosis in Rhesus Macaques

Endometriosis is an estrogen-dependent disorder defined by endometrium-like tissue outside the uterine cavity that results in pelvic inflammation. Pro-inflammatory cytokines can increase 11 β -hydroxysteroid dehydrogenase type 1 (11β-HSD1), which converts inactive cortisone into active cortisol. We hypothesized that cyclic changes in estrogen (estradiol; E2) and progesterone (P4) could regulate endometriotic 11β-HSD1. To test this, we assessed 11β-HSD1 expression in rhesus macaques (Macaca mulatta) with advanced endometriosis. Animal care was provided by our Department of Comparative Medicine and all work was reviewed and approved by the Institutional Animal Care and Use Committee. Endometrium and lesions were collected in the proliferative and secretory phase of the cycle (n=5 each). Control endometrium (endometriosis-free animals) was also collected in the proliferative (n=5) and secretory (n=4) phase. Mean (+SE) hormone levels were: 103+10 pg E2/ml and 0.2 + 0.04 ng P/ml in the proliferative phase; 43.8 + 9 pg E2/ml and 4.41 + 0.98 ng P/ml in the secretory phase. Tissues were frozen in liquid nitrogen for RNA isolation or fixed for histology. RNA was isolated in TRIzol and purified on Qiagen Quick columns with DNase digestion. Total RNA (1 µg) was reverse transcribed in the presence of random hexamer primers. TaqMan® quantitative real-time PCR (q-RT-PCR) was conducted for 11β-HSD1, estrogen receptor 1 (ESR1), ESR2 and progesterone receptor (PGR). Results are presented as ratio of target/ribosomal S10 RNA. Normal cyclic regulation of endometrial histology was observed. Histology confirmed the presence of endometrium-like tissue in all lesions. The highest expression of 11β-HSD1 was in proliferative phase endometriotic lesions (0.64 + 0.28). Levels were reduced in the secretory phase (0.13 + 0.02; P<0.01). 11β-HSD1 was minimal in the endometrium of control and endometriosis animals (proliferative phase control = 0.11 + 0.03; versus endometriotic animals = 0.11+ 0.06). There was a non-significant trend toward higher levels in the secretory phase (control = 0.24+ 0.06; endometriosis = 0.16 + 0.03). Normal cyclic levels of ESR1 and PGR were observed. For instance, levels of ESR1 (proliferative versus secretory) in the control endometrium, endometriosis endometrium, and lesions were as follows: 2.36 + 0.39 versus 0.43 + 0.21 (P<0.01), 1.41 + 0.22 versus 0.74 + 0.34 (P<0.01), and 1.05 + 0.35 versus 0.48 + 0.11(P<0.05); respectively. Levels of PGR followed the pattern of ESR1. In contrast, ESR2 transcript was higher in lesions compared to endometrium, and menstrual cycle-specific regulation was observed. We conclude that 11β-HSD1 is elevated in the proliferative phase resulting in increased intracellular cortisol. Elevated cortisol could promote estrogen dependent lesion growth by modulating inflammation. This work was supported by NIH/NICHD.

Mif deficiency promotes adiposity in fructose-fed mice.

The macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine involved in inflammation, regulation of energy metabolism and glucocorticoid action. Chronic low-grade inflammation may be caused by fructose intake, contributing to visceral adipose tissue (VAT) dysfunction. Since MIF is a known antagonist of glucocorticoid signaling, and deregulated glucocorticoid signaling can contribute to lipid metabolism disturbances, we hypothesized that altered MIF signaling might underlie fructose-induced adiposity through glucocorticoid action. We analyzed physiological and biochemical parameters, adipose tissue histology, insulin sensitivity and lipid metabolism in WT and MIF-/- C57Bl/6J mice consuming 20% fructose solution for 9 weeks. Glucocorticoid prereceptor metabolism and glucocorticoid receptor (GR) protein level were examined in VAT, together with the expression of glucocorticoid-target genes involved in lipid metabolism. The expression of adipogenic and lipogenic transcriptional regulators peroxisome proliferator-activated receptor gamma (PPARG) and sterol regulatory element-binding protein 1c (SREBP1c) was also assessed. Results showed disturbed insulin sensitivity in all MIF-/- mice, regardless of the diet. Mice on fructose diet had increased energy intake, but increased visceral adiposity and enlarged adipocytes were observed only in fructose-fed MIF-/- mice. Increased VAT corticosterone level and 11 beta-hydroxysteroid dehydrogenase type 1, hexose-6-phosphate dehydrogenase and GR protein levels were observed in the same animals, together with induced expression of examined lipogenic genes and accumulation of PPARG and SREBP1c. In conclusion, the results showed that dietary fructose was associated with increased visceral adiposity through activation of GR-regulated lipogenic genes, but only in the absence of MIF, which set the state of hyperinsulinemia and insulin resistance.

Impact of MR on mature adipocytes in high-fat/high-sucrose diet-induced obesity

Active glucocorticoid levels are elevated in the adipose tissue of obesity due to the enzyme 11 beta-hydroxysteroid dehydrogenase type 1. Glucocorticoids can bind and activate both glucocorticoid receptor (GR) and mineralocorticoid receptor (MR), and pharmacological blockades of MR prevent high-fat diet-induced obesity and glucose intolerance. To determine the significance of MR in adipocytes, we generated adipocyte-specific MR-knockout mice (AdipoMR-KO) and fed them high-fat/high-sucrose diet. We found that adipocyte-specific deletion of MR did not affect the body weight, fat weight, glucose tolerance or insulin sensitivity. While liver weight was slightly reduced in AdipoMR-KO, there were no significant differences in the mRNA expression levels of genes associated with lipogenesis, lipolysis, adipocytokines and oxidative stress in adipose tissues between the control and AdipoMR-KO mice. The results indicated that MR in mature adipocytes plays a minor role in the regulation of insulin resistance and inflammation in high-fat/high-sucrose diet-induced obese mice.

Regulatory role of microRNA-320a in the proliferation, migration, invasion, and apoptosis of trophoblasts and endothelial cells by targeting estrogen-related receptor γ.

Recently, microRNAs (miRNAs) have been demonstrated to participate in many physiological and biological processes, especially by acting as circulating biomarkers or modulators in cell differentiation. Therefore, the aim of the current study was to clarify whether microRNA-320a (miR-320a) regulates the proliferation, migration, invasion, and apoptosis of trophoblasts and endothelial cells. In this study, miR-320a mimics and inhibitors were transfected into HTR.8/SVneo cells and human umbilical vein endothelial cells (HUVECs) using liposomes. Subsequently, the expression of miR-320a and estrogen-related receptor γ (ERRγ) mRNA was detected by a reverse transcription quantitative polymerase chain reaction, whereas the protein expression of ERRγ, vascular endothelial growth factor (VEGF), angiogenin 1 (Ang-1), human 3beta-hydroxysteroid dehydrogenase type 1 (HSD3B1), and human chorionic gonadotropin (HCG) was detected by western blot analysis. Furthermore, the proliferation, invasion/migration, and apoptosis of cells were analyzed by the cell counting kit-8 assay, transwell assay, and flow cytometry, respectively. The results showed that overexpression of miR-320a decreased the optical density (OD) values and the proliferation rate of HTR.8/SVneo cells and HUVECs, while inhibiting the expression of VEGF, Ang-1, HSD3B1, and HCG in these cells. Furthermore, miR-320a reduced the ability of cell invasion and migration, while increasing the rate of cell apoptosis. After cotransfecting the cells with miR-320a and ERRγ small (or short) interfering RNA (siRNA), the decreased ERRγ expression led to inhibited proliferation, migration, and invasion, but increased apoptosis of HTR.8/SVneo cells and HUVECs. Our results further revealed that miR-320a induced the apoptosis of trophoblasts and endothelial cells while inhibiting their proliferation, migration, and invasion by decreasing the expression of ERRγ and by indirectly suppressing the expression of VEGF, Ang-1, HSD3B1, and HCG.

Seasonal regulation of steroidogenic enzyme expression within the green anole lizard (Anolis carolinensis) brain and gonad

Steroid hormones, such as testosterone and estradiol, are necessary for reproductive behavior. Seasonally breeding animals have increased sex steroid hormone levels during the breeding compared to non-breeding season, with increased reproductive behaviors and altered brain morphology in breeding individuals. Similar to other seasonally breeding animals, green anole lizards (Anolis carolinensis) have high sex steroid hormone levels and increased reproductive behaviors in the breeding season. Relatively less is known regarding the regulation of steroidogenesis in reptiles and this experiment examined whether enzymes involved in sex steroid hormone synthesis vary seasonally within the brain and gonads in wild-caught anole lizards. Specifically, we examined mRNA expression of steroidogenic acute regulatory protein (StAR), P450 17α-hydroxylase/C17-20lyase (Cyp17α1), 17 beta-hydroxysteroid dehydrogenase type 3 (17βHSD 3), and aromatase (Cyp19α1). We found that the mRNA for each of these genes was expressed in the lizard brain. Interestingly, Cyp19α1 mRNA expression in the brain was increased during the non-breeding season, potentially revealing a role for aromatase expression in the non-breeding brain. In the anole gonads, StAR mRNA expression levels were increased in both males and females during the breeding season, while the mRNA expression levels of CYP17α1 and 17βHSD 3 are increased when StAR mRNA expression was decreased, suggesting that the enzymes in the steroidogenic pathway are potentially regulated independently of StAR. This work reveals the seasonal regulation of steroidogenesis in the reptilian brain and gonad, although more work is necessary to determine the regulatory mechanisms that control these expression patterns.

11 Beta-hydroxysteroid dehydrogenase type 1 regulates synovitis, joint destruction, and systemic bone loss in chronic polyarthritis

ObjectiveIn rheumatoid arthritis, the enzyme 11 beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is highly expressed at sites of inflammation, where it converts inactive glucocorticoids (GC) to their active counterparts. In conditions of GC excess it has been shown to be a critical regulator of muscle wasting and bone loss. Here we examine the contribution of 11β-HSD1 to the pathology of persistent chronic inflammatory disease. MethodsTo determine the contribution of 11β-HSD1 to joint inflammation, destruction and systemic bone loss associated with persistent inflammatory arthritis, we generated mice with global and mesenchymal specific 11β-HSD1 deletions in the TNF-transgenic (TNF-tg) model of chronic polyarthritis. Disease severity was determined by clinical scoring. Histology was assessed in formalin fixed sections and fluorescence-activated cell sorting (FACS) analysis of synovial tissue was performed. Local and systemic bone loss were measured by micro computed tomography (micro-CT). Measures of inflammation and bone metabolism were assessed in serum and in tibia mRNA. ResultsGlobal deletion of 11β-HSD1 drove an enhanced inflammatory phenotype, characterised by florid synovitis, joint destruction and systemic bone loss. This was associated with increased pannus invasion into subchondral bone, a marked polarisation towards pro-inflammatory M1 macrophages at sites of inflammation and increased osteoclast numbers. Targeted mesenchymal deletion of 11β-HSD1 failed to recapitulate this phenotype suggesting that 11β-HSD1 within leukocytes mediate its protective actions in vivo. ConclusionsWe demonstrate a fundamental role for 11β-HSD1 in the suppression of synovitis, joint destruction, and systemic bone loss. Whilst a role for 11β-HSD1 inhibitors has been proposed for metabolic complications in inflammatory diseases, our study suggests that this approach would greatly exacerbate disease severity.

O39 11beta-hydroxysteroid dehydrogenase type 1 regulates the suppression of inflammation, joint destruction and systemic bone loss in a model of chronic inflammation

O39 11beta-hydroxysteroid dehydrogenase type 1 regulates the suppression of inflammation, joint destruction and systemic bone loss in a model of chronic inflammation

11β-HSD Types 1 and 2 in the Songbird Brain.

Glucocorticoid (GC) hormones act on the brain to regulate diverse functions, from behavior and homeostasis to the activity of the hypothalamic–pituitary–adrenal axis. Local regeneration and metabolism of GCs can occur in target tissues through the actions of the 11β-hydroxysteroid dehydrogenases [11 beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and 11 beta-hydroxysteroid dehydrogenase type 2 (11β-HSD2), respectively] to regulate access to GC receptors. Songbirds have become especially important model organisms for studies of stress hormone action; however, there has been little focus on neural GC metabolism. Therefore, we tested the hypothesis that 11β-HSD1 and 11β-HSD2 are expressed in GC-sensitive regions of the songbird brain. Localization of 11β-HSD expression in these regions could provide precise temporal and spatial control over GC actions. We quantified GC sensitivity in zebra finch (Taeniopygia guttata) brain by measuring glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) expression across six regions, followed by quantification of 11β-HSD1 and 11β-HSD2 expression. We detected GR, MR, and 11β-HSD2 mRNA expression throughout the adult brain. Whereas 11β-HSD1 expression was undetectable in the adult brain, we detected low levels of expression in the brain of developing finches. Across several adult brain regions, expression of 11β-HSD2 covaried with GR and MR, with the exception of the cerebellum and hippocampus. It is possible that receptors in these latter two regions require direct access to systemic GC levels. Overall, these results suggest that 11β-HSD2 expression protects the adult songbird brain by rapid metabolism of GCs in a context and region-specific manner.

Association of HSD11B1 rs12086634 and HSD11B1 rs846910 gene polymorphisms with polycystic ovary syndrome in South Indian women

The 11beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme generates cortisol from cortisone for local glucocorticoid action in hepatocytes and adipocytes. Functional polymorphisms within 11beta-hydroxysteroid dehydrogenase type 1 (HSD11B1) gene have shown an association with various factors including insulin resistance, diabetes, and obesity. In this study, we have assessed a candidate gene association study in order to examine the association of HSD11B1 gene polymorphisms with polycystic ovary syndrome (PCOS). A total of 200 women were investigated in this case-control study. DNA samples from PCOS women (n = 100) and the age-matched control women (n = 100) were analyzed. Genotyping of HSD11B1 rs12086634 and rs846910 variants was performed using tetra-primer amplification refractory mutation system (TETRA-ARMS) PCR. Odds ratio and 95% confidence interval were calculated to determine the association of HSD11B1 gene polymorphisms with polycystic ovary syndrome. The association analysis indicate that HSD11B1 rs12086634 showed positive association with polycystic ovary syndrome (OR = 1.95; 95%CI = 1.11–3.44, p = 0.0195) and women with HSD11B1 rs12086634 TG genotype had significantly higher body mass index (28.05 kg/mt2, p = 0.001), higher waist circumference (89.68 cms, p = 0.019), higher triglycerides (120.37 mg/dl, p = 0.049), and lower HDL levels (45.56 mg/dl, p = 0.004) compared to the women with HSD11B1 TT genotype. HSD11B1 rs846910 did not show any association with PCOS (OR = 0.57; 95%CI = 0.311–1.051, p = 0.072). Our results suggest that HSD11B1 rs12086634 polymorphism is associated with PCOS and HSD11B1 rs846910 gene polymorphism is not associated with PCOS in South Indian women.

A Network Pharmacology Approach to Determine the Active Components and Potential Targets of Curculigo Orchioides in the Treatment of Osteoporosis.

BackgroundOsteoporosis is a complex bone disorder with a genetic predisposition, and is a cause of health problems worldwide. In China, Curculigo orchioides (CO) has been widely used as a herbal medicine in the prevention and treatment of osteoporosis. However, research on the mechanism of action of CO is still lacking. The aim of this study was to identify the absorbable components, potential targets, and associated treatment pathways of CO using a network pharmacology approach.Material/MethodsWe explored the chemical components of CO and used the five main principles of drug absorption to identify absorbable components. Targets for the therapeutic actions of CO were obtained from the PharmMapper server database. Pathway enrichment analysis was performed using the Comparative Toxicogenomics Database (CTD). Cytoscape was used to visualize the multiple components-multiple target-multiple pathways-multiple disease network for CO.ResultsWe identified 77 chemical components of CO, of which 32 components could be absorbed in the blood. These potential active components of CO regulated 83 targets and affected 58 pathways. Data analysis showed that the genes for estrogen receptor alpha (ESR1) and beta (ESR2), and the gene for 11 beta-hydroxysteroid dehydrogenase type 1, or cortisone reductase (HSD11B1) were the main targets of CO. Endocrine regulatory factors and factors regulating calcium reabsorption, steroid hormone biosynthesis, and metabolic pathways were related to these main targets and to ten corresponding compounds.ConclusionsThe network pharmacology approach used in our study has attempted to explain the mechanisms for the effects of CO in the prevention and treatment of osteoporosis, and provides an alternative approach to the investigation of the effects of this complex compound.

Glucocorticoids activation by 11beta-hydroxysteroid dehydrogenase type 1 protects against inflammatory bone loss in a murine model of chronic inflammation

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Ultraviolet- and infrared-induced 11 beta-hydroxysteroid dehydrogenase type 1 activating skin photoaging is inhibited by red ginseng extract containing high concentration of ginsenoside Rg3(S).

Sun irradiation is one of major extrinsic stressors responsible for premature skin aging through activation and expression of 11 beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which converts inactive cortisone to active cortisol. The aim of this study was to evaluate the inhibitory effects of red ginseng extract containing high concentrations of ginsenoside Rg3 (S) (GERg3) on 11β-HSD1-induced skin photoaging. To evaluate the inhibitory effects of GERg3 on ultraviolet- (UV) or infrared (IR)-induced skin photoaging, human dermal fibroblasts or a normal human 3D skin model was exposed to UV or an IR. RT-PCR, ELISA, Western blot, and H&E staining were used for evaluations. GERg3 was isolated from crude red ginseng. GERg3 inhibited the increased expressions of 11β-HSD1, interleukin (IL)-6, and matrix metalloproteinase-1 (MMP-1) in UVB- or IR-exposed Hs68 cells. Additionally, the increased cortisol, IL-6, and MMP-1 expressions were effectively reduced by GERg3 in UVA-exposed 3D skin models. The photoinduced decrease in type 1 procollagen also recovered as a result of GERg3 treatment in Hs68 cells and the 3D skin model. In addition, the UVA-exposed dermal thickness was decreased in comparison with the UVA-protected 3D skin model, recovered with GERg3 treatment. GERg3 had antiphotoaging effects in UV- or IR-exposed human dermal fibroblasts and normal human 3D skin model.

P6288Rac1 GTPase regulates 11beta Hydroxysteroid Dehydrogenase Type 2, which is associated with structural cardiac remodeling

P6288Rac1 GTPase regulates 11beta Hydroxysteroid Dehydrogenase Type 2, which is associated with structural cardiac remodeling

Beneficial metabolic effects of dietary epigallocatechin gallate alone and in combination with exendin-4 in high fat diabetic mice

ObjectiveSignificant attempts are being made to generate multifunctional, hybrid or peptide combinations as novel therapeutic strategies for type 2 diabetes, however this presents key challenges including design and pharmaceutical development. In this study, we evaluated metabolic properties of oral nutritional supplement epigallocatechin gallate (EGCG) in combination with GLP-1 agonist exendin-4 in a mouse model of dietary-induced diabetes and obesity. MethodsEGCG, exendin-4 or combination of both were administered twice-daily over 28 days to high fat (HF) mice on background of low-dose streptozotocin. Energy intake, body weight, fat mass, glucose tolerance, insulin sensitivity, lipid profile, biochemical and hormone markers, and islet histology were examined. ResultsAll treatment groups exhibited significantly reduced body weight, fat mass, circulating glucose and insulin concentrations, and HbA1c levels which were independent of changes in energy intake. Similarly, there was marked improvement in glycaemic control, glucose-stimulated insulin release, insulin sensitivity, total cholesterol and triglycerides, with most prominent effects observed following combination therapy. Circulating corticosterone concentrations and 11beta-hydroxysteroid dehydrogenase type1 (11β-HSD1) staining (in pancreas) were beneficially decreased without changes in circulating interleukin 6 (IL-6), alanine transaminase (ALT) and glutathione reductase. Combination therapy resulted in increased islet area and number, beta cell area, and pancreatic insulin content. Generally, metabolic effects were much more pronounced in mice which received combination therapy. ConclusionsEGCG alone and particularly in combination with exendin-4 exerts positive metabolic properties in HF mice. EGCG may be useful dietary adjunct alongside GLP-1 mimetics in treatment of diabetes and related disorders.