Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:Q7LGC8 (HSD)
 3,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In vitro germinal vesicle breakdown (GVBD) in Cyprinus carpio oocytes was induced by recombinant human insulin-like growth factor-I and -II (IGF-I and IGF-II) and bovine insulin (b-insulin). Treatment of postvitellogenic ovarian follicles with IGF-I and b-insulin increased concentration of maturation-inducing hormone (MIH), 17alpha,20beta-dihydroxy-4-pregnane-3-one (DHP) in the medium. IGF-I and IGF-II both and b-insulin induced GVBD in denuded oocytes. IGF-I analogue R3 IGF-I was more potent than IGF-I in inducing GVBD of postvitellogenic follicles suggesting that ovarian IGF binding proteins may inhibit IGF-I action. Vitellogenic follicles, which were immature for oocytes to complete GVBD in response to DHP or HCG, underwent GVBD by IGF-I, not by b-insulin. IGF-I was also able to stimulate DHP production in such follicles. Addition of DHP and HCG to the culture of vitellogenic follicles containing IGF-I or b-insulin did neither potentiate the stimulation of GVBD induced by IGF-I nor initiate the same in response to b-insulin. Incubation of postvitellogenic follicles with trilostane (3beta-HSD inhibitor) had no inhibitory effects on IGF-I- and b-insulin-induced GVBD but attenuated the same under HCG stimulation. Trilostane, however, strongly inhibited DHP production induced by all these effectors. Induction of GVBD by IGF-I and b-insulin was not altered in the presence of actinomycin D. However, it significantly blocked the HCG-induced GVBD. Cycloheximide was shown to inhibit the induction of GVBD and DHP production by IGF-I, b-insulin and HCG. Both actinomycin D and cycloheximide were found to inhibit DHP production stimulated by all the three effectors. Collectively, these observations indicate that IGF-I and b-insulin can induce GVBD via MIH- and transcription-independent pathway. Incubation of the follicles with gap junction uncouplers, 1-heptanol or 1-octanol, had no effect on IGF-I- and b-insulin-induced GVBD, but attenuated the same induced by HCG. These uncouplers, however, inhibited DHP production induced by IGF-I, b-insulin and HCG. This result suggests that both IGF-I and b-insulin can induce oocyte maturation without coupled gap junction between oocytes and granulosa cells, while homologous gap junctions are required for DHP production. Inhibitors of phosphatidylinositol-3 kinase (PI-3 kinase), wortmannin and LY294002 inhibited GVBD by IGF-I and b-insulin. These two inhibitors also attenuated HCG-induced GVBD. These data suggest that PI-3 kinase activity is required for IGF-I, b-insulin and HCG induction of GVBD in C. carpio.
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PMID:In vitro effects of insulin-like growth factors and insulin on oocyte maturation and maturation-inducing steroid production in ovarian follicles of common carp, Cyprinus carpio. 1653 Oct 89

Our purpose was to investigate the effects of electroacupuncture (EA) therapy on body weight and on levels of serum insulin, c-peptide and glucose in obese women. 52 healthy women were included in this study and were allocated into three groups: 1) Placebo EA group (n = 15; mean age = 41.8 +/- 4.6 and mean body mass index {BMI} = 33.2 +/- 3.5); 2) EA group (n = 20; mean age = 42.1 +/- 4.4 and BMI = 35.9 +/- 3.6) and 3) Diet restriction group (n = 20; mean age = 42.9 +/- 4.3 and BMI = 34.7 +/- 2.7). EA was applied to the ear points Hunger and Shen Men on alternating days and to the body points LI 4, LI 11, St 36 and St 44 once a day for 30 minutes over 20 days. Diet restriction that entailed a 1450 kilocalorie (kcal) diet program was applied to the three groups for 20 days. An increase in weight loss was observed when weight loss in the EA group (p < 0.000) was compared to that in the diet restricted and placebo EA groups using the Tukey HSD test. There were increases in the serum insulin (p < 0.001) and c-peptide levels (p < 0.000) in the women treated with EA compared to those in the women treated with the placebo EA and diet restriction groups. A decrease was observed in the glucose levels (p < 0.01) in both the EA and diet restriction groups compared to those in the placebo EA group. Our results suggest that EA therapy is an effective method in treating obesity. EA therapy also helps serum glucose levels to decrease through the increase of serum insulin and c-peptide levels.
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PMID:Changes in levels of serum insulin, C-Peptide and glucose after electroacupuncture and diet therapy in obese women. 1671 Aug 86

The third annual meeting of the Androgen Excess Society, held in San Diego, California, June 3, 2005, reported on new developments in the field, including intrafollicular steroidogenesis, intrathecal biochemistry, mechanisms of insulin signal and resistance of polycystic ovary syndrome, and novel aspects of androgen signaling. The experience of the 21-OH-deficient Nonclassical Adrenal Hyperplasia (NCAH) Multicenter Study Group was also discussed, along with a keynote presentation on the molecular aspects of 3beta-HSD-deficient NCAH.
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PMID:Report on the Third Annual Meeting of the Androgen Excess Society, San Diego, California, June 3, 2005. 1707 Jan 90

Syndrome X, the Metabolic Syndrome, and type II diabetes are closely related diseases that share risk factors and symptoms, notably insulin resistance. Several factors have been proposed either to mediate the disease(s) or to be their causes, and most converge on the endocrine/paracrine functions of the adipocyte. A common feature of such systems is their relative autonomy from systemic negative feedback regulation, for example by the HPA axis. We draw particular attention to two such mechanisms, both of which are associated with, and can cause, insulin resistance: the extra-adrenal production of corticosteroids, and the tissue renin angiotensin system of the adipocyte. These show another feature: the inter-regulation of glucocorticoid action and the RAS by positive feedback. Cortisol enhances the expression of 11 beta-HSD 1, and also of angiotensinogen and angiotensin type 1 receptors. In turn, angiotensin can stimulate further corticosteroid production, from the adrenal and perhaps from extra-adrenal sources. The instability inherent in such positive loops could account for the progressive nature of the disease(s), suggesting ways to break the circle.
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PMID:Angiotensin II, corticosteroids, type II diabetes and the metabolic syndrome. 1713 48

Adverse influences during fetal life alter the structure and function of distinct cells, organ systems or homoeostatic pathways, thereby 'programming' the individual for an increased risk of developing cardiovascular disease and diabetes in adult life. Fetal programming can be caused by a number of different perturbations in the maternal compartment, such as altered maternal nutrition and reduced utero-placental blood flow; however, the underlying mechanisms remain to be fully established. Perturbations in the maternal environment must be transmitted across the placenta in order to affect the fetus. Here, we review recent insights into how the placenta responds to changes in the maternal environment and discuss possible mechanisms by which the placenta mediates fetal programming. In IUGR (intrauterine growth restriction) pregnancies, the increased placental vascular resistance subjects the fetal heart to increased work load, representing a possible direct link between altered placental structure and fetal programming of cardiovascular disease. A decreased activity of placental 11beta-HSD-2 (type 2 isoform of 11beta-hydroxysteroid dehydrogenase) activity can increase fetal exposure to maternal cortisol, which programmes the fetus for later hypertension and metabolic disease. The placenta appears to function as a nutrient sensor regulating nutrient transport according to the ability of the maternal supply line to deliver nutrients. By directly regulating fetal nutrient supply and fetal growth, the placenta plays a central role in fetal programming. Furthermore, perturbations in the maternal compartment may affect the methylation status of placental genes and increase placental oxidative/nitrative stress, resulting in changes in placental function. Intervention strategies targeting the placenta in order to prevent or alleviate altered fetal growth and/or fetal programming include altering placental growth and nutrient transport by maternally administered IGFs (insulin-like growth factors) and altering maternal levels of methyl donors.
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PMID:Role of the placenta in fetal programming: underlying mechanisms and potential interventional approaches. 1753 98

The 11beta-hydroxysteroid dehydrogenase (11beta-HSD) exists in two isoforms, 11beta-HSD1 and 11beta-HSD2. 11beta-HSD1 generates active cortisol from cortisone and appears to be involved in insulin resistant states. 11beta-HSD2 protects the mineralocorticoid receptor from inappropriate activation by glucocorticoids and is important to prevent sodium retention and hypertension. The purposes of the present study were to develop two real-time PCR assays to assess 11beta-HSD1 and 11beta-HSD2 mRNA expression and to evaluate the tissue distribution of the two isoforms in dogs. Thirteen different tissues of 10 healthy dogs were evaluated. Both real-time PCR assays were highly specific, sensitive and reproducible. Highest 11beta-HSD1 mRNA expression was seen in liver, lung, and renal medulla; highest 11beta-HSD2 mRNA expression in renal cortex, adrenal gland, and renal medulla. Higher 11beta-HSD1 than 11beta-HSD2 mRNA levels were found in all tissues except adrenal gland, colon, and rectum. Our results demonstrate that the basic tissue distribution of 11beta-HSD1 and 11beta-HSD2 in dogs corresponds to that in humans and rodents. In a next step 11beta-HSD1 and 11beta-HSD2 expression should be assessed in diseases like obesity, hypercortisolism, and hypertension to improve our knowledge about 11beta-HSD activity, to evaluate the dog as a model for humans and to potentially find new therapeutic options.
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PMID:Quantitative real-time PCR for the measurement of 11beta-HSD1 and 11beta-HSD2 mRNA levels in tissues of healthy dogs. 1771 18

Glucocorticoids, which are well established to regulate body fat mass distribution, adipocyte lipolysis, hepatic gluconeogenesis, and hepatocyte VLDL secretion, are speculated to play a role in the pathology of metabolic syndrome. Recent focus has been on the activity of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), which is capable of regenerating, and thus amplifying, glucocorticoids in key metabolic tissues such as liver and adipose tissue. To determine the effects of global 11beta-HSD1 inhibition on metabolic syndrome risk factors, we subcutaneously injected "Western"-type diet-fed hyperlipidemic mice displaying moderate or severe obesity [LDL receptor (LDLR)-deficient (LDLR(-/-)) mice and mice derived from heterozygous agouti (A(y)/a) and homozygous LDLR(-/-) breeding pairs (A(y)/a;LDLR(-/-) mice)] with the nonselective 11beta-HSD inhibitor carbenoxolone for 4 wk. Body composition throughout the study, end-point fasting plasma, and extent of hepatic steatosis and atherosclerosis were assessed. This route of treatment led to detection of high levels of carbenoxolone in liver and fat and resulted in decreased weight gain due to reduced body fat mass in both mouse models. However, only A(y)/a;LDLR(-/-) mice showed an effect of 11beta-HSD1 inhibition on fasting insulin and plasma lipids, coincident with a reduction in VLDL due to mildly increased VLDL clearance and dramatically decreased hepatic triglyceride production. A(y)/a;LDLR(-/-) mice also showed a greater effect of the drug on reducing atherosclerotic lesion formation. These findings indicate that subcutaneous injection of an 11beta-HSD1 inhibitor allows for the targeting of the enzyme in not only liver, but also adipose tissue, and attenuates many metabolic syndrome risk factors, with more pronounced effects in cases of severe obesity and hyperlipidemia.
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PMID:Carbenoxolone treatment attenuates symptoms of metabolic syndrome and atherogenesis in obese, hyperlipidemic mice. 1787 20

The present study was designed to investigate the dose-dependent direct effect of corticosterone on the expression of peptide hormone receptors, 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) and glucose oxidation in cultured adult rat Leydig cells. Leydig cells were isolated from the testis of normal adult male albino rats, purified on discontinuous Percoll gradient and plated in culture plates/flasks overnight at 34 degrees C in a CO(2) incubator under 95% air and 5% CO(2) using DME/F12 medium containing 1% fetal bovine serum. After the attachment of cells, serum containing medium was removed and cells were exposed to different doses (0, 50, 100, 200, 400 and 800 nM) of corticosterone using serum-free fresh medium for 24h at 34 degrees C. At the end of exposure period, cells were utilized for the quantification of cell-surface LH, prolactin, insulin receptors and their mRNA expression, the activity and mRNA expression of 11 beta-HSD and glucose oxidation. Testosterone production was estimated in cell pellets and in culture media. At all doses employed, corticosterone significantly decreased the production of testosterone by Leydig cells. The concentration of cell-surface LH and prolactin receptors were significantly reduced after corticosterone exposure whereas the concentration of insulin receptor was diminished only at 200-800 nM doses of corticosterone. The levels of LH and prolactin receptor mRNAs were significantly decreased after corticosterone (100-800 nM) exposure whereas the mRNA level of insulin receptor was significantly reduced only at 800 nM dose of corticosterone. 11 beta-HSD mRNA expression as well as the activity was significantly inhibited by corticosterone treatment. Glucose oxidation was markedly inhibited by corticosterone exposure in a dose-dependent manner. It is concluded from this in vitro study that corticosterone induces steroidogenic lesion in testicular Leydig cells by decreasing the number of cell-surface LH, prolactin and insulin receptors, the activity of 11 beta-HSD and their mRNA levels and glucose oxidation.
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PMID:Corticosterone has direct inhibitory effect on the expression of peptide hormone receptors, 11 beta-HSD and glucose oxidation in cultured adult rat Leydig cells. 1795 Sep 91

In C. elegans, steroid hormones function in conjunction with insulin/IGF-1-like signaling in promoting reproductive development over entry into the diapausal dauer stage. The NCR-1 and -2 (NPC1-related) intracellular cholesterol transporters function redundantly in preventing dauer arrest, presumably by regulating the availability of substrates for steroid hormone synthesis. We have identified hsd-1 as a new component of this cholesterol trafficking/processing pathway, using an ncr-1 enhancer screen. HSD-1 is orthologous to 3beta-hydroxysteroid dehydrogenase/Delta(5)-Delta(4) isomerases (3beta-HSDs), which are key steroidogenic enzymes in vertebrates, and is exclusively expressed in two neuron-like XXX cells that are crucial in preventing dauer arrest, suggesting that it is involved in biosynthesis of dauer-preventing steroid hormones. The hsd-1 null mutant displays defects in inhibiting dauer arrest: it forms dauers in the deletion mutant backgrounds of ncr-1 or daf-28/insulin; as a single mutant, it is hypersensitive to dauer pheromone. We found that hsd-1 defects can be rescued by feeding mutant animals with several steroid intermediates that are either downstream of or in parallel to the 3beta-HSD function in the dafachronic acid biosynthetic pathway, suggesting that HSD-1 functions as a 3beta-HSD. Interestingly, sterols that rescued hsd-1 defects also bypassed the need for the NCR-1 and/or -2 functions, suggesting that HSD-1-mediated steroid hormone production is an important functional output of the NCR transporters. Finally, we found that the HSD-1-mediated signal activates insulin/IGF-I signaling in a cell non-autonomous fashion, suggesting a novel mechanism for how these two endocrine pathways intersect in directing development.
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PMID:Genetic identification of HSD-1, a conserved steroidogenic enzyme that directs larval development in Caenorhabditis elegans. 1849 18

11beta-Hydroxysteroid dehydrogenases (11beta-HSDs) are key enzymes regulating the pre-receptor metabolism of glucocorticoid hormones, which play essential roles in various vital physiological processes. The modulation of 11beta-HSD type 1 activity with selective inhibitors has beneficial effects on various conditions including insulin resistance, dyslipidemia and obesity. Therefore, inhibition of tissue-specific glucocorticoid action by regulating 11beta-HSD1 constitutes a promising treatment for metabolic and cardiovascular diseases. Here we report the discovery of a series of novel adamantyl carboxamides as selective inhibitors of human 11beta-HSD1 in HEK-293 cells transfected with the HSD11B1 gene. Compounds 9 and 14 show inhibitory activity against 11beta-HSD1 with IC(50) values in 100nM range. Docking studies with the potent compound 8 into the crystal structure of human 11beta-HSD1 (1XU9) reveals how the molecule may interact with the enzyme and cofactor.
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PMID:Discovery of novel inhibitors of human 11beta-hydroxysteroid dehydrogenase type 1. 1877 71


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