Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P01189 (beta-endorphin)
21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The human placenta contains two types of 11beta-hydroxysteroid dehydrogenase (11beta-HSD). The exclusive oxidase 11beta-HSD2 has been suggested to protect the fetus from high levels of maternal glucocorticoids by converting cortisol to inactive cortisone. Perfused term human placenta was used to examine the activity of the oxoreductase 11beta-HSD1 and to determine the regulation of cortisol effects on placental vascular tone and corticotropin-releasing hormone (CRH) output by 11beta-HSD. Radioimmunoassay showed that there was substantial cortisol (295+/-57 nM) detected in the fetal vein upon perfusion of cortisol (2 microM; perfusion rate, 12 ml/min) into the maternal intervillous space. Output of cortisol increased to 559+/-22 nM on the fetal side (P<0.05) with concurrent perfusion of carbenoxolone (CBX; 1 microM), a non-specific 11beta-HSD inhibitor. Cortisol formation increased in a dose-dependent manner with infusion of cortisone (0.1-2 microM) into the maternal intervillous space reaching 15 and 23 nM in fetal and maternal venous outflows respectively at 2 microM cortisone perfusion. There was no significant effect of cortisol either alone or in combination with CBX on the fetal arterial perfusion pressure, but cortisol perfusion increased CRH output into the fetal vein. It is concluded that activities of both 11beta-HSD1 and -2 are demonstrable in perfused human placenta in vitro, and these enzymes affect transplacental glucocorticoid transfer. These activities may provide a precise mechanism to control the passage of maternal glucocorticoids to the fetal circulation, and to regulate glucocorticoid effects within the placenta.
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PMID:Interconversion of cortisol and cortisone by 11beta-hydroxysteroid dehydrogenases type 1 and 2 in the perfused human placenta. 995 Jan 40

The purpose of this work was to compare the plasma adrenocorticotropin (ACTH), corticosterone and interleukin-6 (IL-6) responses that rats of the outbred Sprague-Dawley strain obtained from two different vendors: Charles River (CR) and Harlan (HSD). Basal plasma ACTH and IL-6 concentrations were similar in rats from either vendor (HSD or CR), while CR animals exhibited slightly elevated corticosterone levels in late afternoon. Inflammatory stimuli such as lipopolysaccharide (LPS) (1 microgram/kg, i.v.) or turpentine (50 microliter/100 g, i.m.) which induce the production of endogenous cytokines, produced a significantly larger ACTH response in CR, compared to HSD rats, while the overall corticosterone responses were comparable in both rat groups. This could probably not be accounted for by a greater ACTH responsiveness in CR rats per se because CR and HSD rats showed similar peak ACTH responses to electrofootshock. Furthermore, in contrast to when the stimulus was one that induced endogenous cytokine production, the administration of exogenous interleukin-1beta (IL-1beta, 200 ng/kg, i.v.) produced a 2-fold greater rise in plasma ACTH concentrations in HSD rats compared to CR rats. The plasma IL-6 responses to the inflammatory stimuli showed a similar pattern to ACTH, with LPS and turpentine tending to pruduce greater IL-6 responses in CR rats, though these differences were not statistically significant. In contrast HSD rats had a significantly greater IL-6 response to IL-1beta than did CR rats. Collectively, these results show that Sprague-Dawley rats obtained from different commercial sources can differ in immune-neuroendocrine responses to inflammatory stimuli.
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PMID:Sprague-Dawley rats obtained from different vendors exhibit distinct adrenocorticotropin responses to inflammatory stimuli. 1051 81

Adrenarche is characterized by a prepubertal rise in adrenal secretion of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) that is independent of the gonads or gonadotropins. Adrenopause is the corresponding diminution in DHEA and DHEAS concentrations in later life. The mechanisms by which adrenarche and adrenopause are induced and regulated are unknown. Early work focused on identifying hypothetical adrenal androgen regulatory hormones that would induce DHEA in much the same way that adrenocorticotropin induces cortisol, but no such factors have been found. Current studies of adrenarche focus on intra-adrenal events, particularly those concerning 3beta-hydroxysteroid dehydrogenase (3beta-HSD) and 17alpha-hydroxylase/17,20-lyase (P450c17). Molecular data implicate a decrease in 3beta-HSD specifically in the adrenal zona reticularis. However, a decrease in 3beta-HSD is insufficient to explain why the reticularis catalyzes 17,20-lyase activity and hence makes DHEA, rather than catalyzing only 17alpha-hydroxylase activity, as does the zona fasciculata. P450c17 appears to catalyze 17,20-lyase activity only if P450c17 has undergone serine phosphorylation and has access to cytochrome b5 as an allosteric cofactor. Although these two factors have not yet been investigated in adrenarche, it appears that both a zone-specific diminution in 3beta-HSD and a zone-specific induction of 17,20-lyase activity are required to account for the physiological data. Exaggerated premature adrenarche appears to be an early sign of polycystic ovary syndrome (PCOS). Mechanistic considerations of PCOS suggest a key role for serine phosphorylation of P450c17 in both adrenarche and some forms of heritable PCOS.
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PMID:The molecular basis of premature adrenarche: an hypothesis. 1062 47

Glucocorticoids may underlie the association between prenatal stress, low birth weight and adult stress-associated disorders, e.g. hypertension and type 2 diabetes, increased hypothalamic-pituitary-adrenal (HPA) activity and affective dysfunction. Normally, 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) rapidly inactivates glucocorticoids in placenta and many foetal tissues, thus acting as a 'barrier' to maternal steroids. We investigated the effect of inhibiting foeto-placental 11beta-HSD in rats, using carbenoxolone (CBX), on subsequent HPA activity and regulation and stress-induced behaviour in adult offspring. Pregnant Wistar rats were injected with CBX (12.5 mg s.c.) or vehicle daily throughout pregnancy. CBX treatment reduced birth weight. Adult offspring of CBX-treated dams had persistently reduced body weight, increased basal corticosterone (CORT) levels, increased corticotropin-releasing hormone (CRH) and reduced glucocorticoid receptor (GR) mRNA in the hypothalamic paraventricular nucleus, though hippocampal GR and mineralocorticoid receptor (MR) mRNA expression were unaltered. In addition, these animals showed less grooming and rearing in an open field and reduced immobility in a forced swim test, and had increased GR mRNA expression in the basolateral (BLA), central (CEA) and medial (MEA) nuclei of the amygdala, with unaltered MR mRNA. These data suggest that disturbance of the foeto-placental enzymatic barrier to maternal glucocorticoids reduces birth and body weight, and produces permanent alterations of the HPA axis and anxiety-like behaviour in aversive situations. The behavioural and HPA effects may reflect GR gene programming in amygdala and hypothalamus, respectively. Foetal overexposure to endogenous glucocorticoids (prenatal stress or reduced activity of foeto-placental 11beta-HSD) may represent a common link between the prenatal environment, foetal growth and adult neuroendocrine and affective disorders.
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PMID:Inhibition of 11beta-hydroxysteroid dehydrogenase, the foeto-placental barrier to maternal glucocorticoids, permanently programs amygdala GR mRNA expression and anxiety-like behaviour in the offspring. 1076 36

The hypothalamic-pituitary-adrenal axis is hyporesponsive to stress in late pregnancy, exemplified as reduced adrenocorticotropic hormone (ACTH) and corticosterone responses to restraint, but the mechanisms are unknown. We investigated forward drive and negative feedback upon the hypothalamic-pituitary-adrenal axis in pregnant rats. Corticotropin-releasing hormone (CRH) and vasopressin mRNA expression in the parvocellular paraventricular nucleus and mineralocorticoid and glucocorticoid receptor expression in the paraventricular nucleus and hippocampus were quantified with in situ hybridization. Because it can enhance the corticosterone negative feedback signal, 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) bioactivity in these brain regions and anterior pituitary was measured in vitro, and ACTH and corticosterone stress responses were measured after intracerebroventricular glycyrrhetinic acid, an 11beta-HSD inhibitor. Changes in corticosterone feedback on ACTH secretion were examined after pharmacological adrenalectomy by metyrapone and aminoglutethimide. Parvocellular paraventricular nucleus CRH mRNA content was reduced on day 21 and the CRH mRNA : vasopressin mRNA ratio was unaltered, indicating decreased production of both CRH and vasopressin. An increase in glucocorticoid receptor mRNA expression in the dentate gyrus (mineralocorticoid receptor mRNA expression was unaltered) and increased 11beta-HSD1 activity in the paraventricular nucleus and anterior pituitary suggest an increase in slow negative feedback mechanisms in pregnancy, but glycyrrhetinic acid did not modify the stress response. After metyrapone/aminoglutethimide treatment, corticosterone decreased ACTH secretion more slowly in pregnancy, indicating a decrease in rapid feedback sensitivity. Thus, reduced forward drive rather than increased effectiveness of glucocorticoid negative feedback may underlie stress hyporesponsiveness of the hypothalamic-pituitary-adrenal axis in pregnancy.
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PMID:Attenuation of hypothalamic-pituitary-adrenal axis stress responses in late pregnancy: changes in feedforward and feedback mechanisms. 1092 94

The messenger RNA abundance of proopiome-lanocortin (POMC) is increased in neurointermediate lobe (NIL) of rat pituitary when ingesting a high sodium diet (8%; HSD), as is the plasma concentration of the natriuretic peptide gamma-melanocyte stimulating hormone (gammay-MSH) derived from it. We examined whether the HSD also increases the mRNA abundance in rat NIL of proconvertases 1 and 2 (PC1, PC2), enzymes involved in the processing of POMC into gamma-MSH. PC1 mRNA increased by 40% after two weeks of the HSD and by 84% after three weeks. PC2 mRNA increased by 40% after two weeks and by more than 3 fold after three weeks. These results for PC2 were confined to NIL as shown by in situ hybridization at one and two weeks, and were accompanied by a significant increase in NIL PC2 protein after three weeks of the HSD as measured by immunoblotting. The increases in PC1 and PC2 mRNA abundance were paralleled by an increase in POMC mRNA level in NIL. Plasma gamma-MSH immunoreactivity averaged 35.1 +/- 3.3 fmol/ml in rats on the LSD, but increased to 70.9 +/- 4.8 fmol/ml after 3 weeks of the HSD (p < 0.002 vs LSD). These results confirm that the HSD increases the plasma concentration of gamma-MSH, consistent with a role for it as a circulating natriuretic peptide. The increased NIL expression of PC1 and PC2 in parallel with POMC in response to the HSD suggests that these changes are part of the coordinated response to states of sodium surfeit.
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PMID:Dietary sodium modulates mRNA abundance of enzymes involved in pituitary processing of proopiomelanocortin. 1250 73

The gamma-melanocyte-stimulating hormone (gamma-MSH) is a natriuretic peptide derived from the N-terminal region of proopiomelanocortin (POMC). Evidence suggests that it may be part of the coordinated response to a low-sodium diet (LSD). We tested the effect of the HSD (8% NaCl) compared with LSD (0.07%) on mean arterial pressure (MAP) in mice with targeted disruption of the PC2 gene (PC2(-/-)), necessary for processing of POMC into gamma-MSH, or the melanocortin receptor 3 gene (Mc3r(-/-); the receptor for MSH). In wild-type mice, HSD for 1 week did not alter MAP versus LSD mice, but plasma gamma-MSH immunoreactivity was more than double the LSD value. In contrast, in PC2(-/-) mice, MAP on the LSD was not greater than in wild-type mice, but plasma gamma-MSH was reduced to one-seventh the wild-type value. On the HSD, MAP rose to a markedly hypertensive level while plasma gamma-MSH concentration remained severely depressed. Intravenous infusion of gamma-MSH (0.2 pmol/min) for 30 min to PC2(-/-) mice after 1 week of HSD lowered MAP from hypertensive levels to normal; infusion of alpha-MSH at the same rate had no effect. Injection of 60 fmol of gamma-MSH into the lateral cerebral ventricle of hypertensive mice also lowered MAP to normal. Administration of a stable analogue of gamma-MSH intra-abdominally by microosmotic pump to PC2(-/-) mice prevented the development of hypertension when ingesting the HSD. In mice with targeted disruption of the Mc3r gene, the HSD also led to marked hypertension accompanied by elevated plasma levels of gamma-MSH; infusion of exogenous gamma-MSH to these mice had no effect on MAP. These results strongly suggest that PC2-dependent processing of POMC into gamma-MSH is necessary for the normal response to the HSD. gamma-MSH deficiency results in marked salt-sensitive hypertension that is rapidly improved with exogenous gamma-MSH through a central site of action. alpha-MSH infused at the same rate had no effect on MAP, indicating that the hypertension is a specific consequence of impaired POMC processing into gamma-MSH. Absence of Mc3r produces gamma-MSH resistance and hypertension on the HSD. These findings demonstrate a novel pathway mediating salt-sensitivity of blood pressure.
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PMID:Genetic disruption of gamma-melanocyte-stimulating hormone signaling leads to salt-sensitive hypertension in the mouse. 1269 27

Petasites hybridus is used in Chinese herbal medicine. S-petasin is a bioactive compound isolated from leaves or roots of Petasites hybridus. S-petasin has been used to relieve gastrointestinal pain, lung disease, and spasms of the urogenital tract. However, the side effect of S-petasin on endocrine systems are still not clear. This study explored the effects of S-petasin on the release of corticosterone in vivo and in vitro. An intravenous injection of S-petasin (10 microg/kg) decreased both basal and adrenocorticotropin (ACTH)-induced plasma corticosterone concentration in male rats. In vitro, S-petasin (3 x 10(-6) - 10(-4) M) caused a significant reduction of basal and ACTH-stimulated release of corticosterone from the enzymatically dispersed rat zona fasciculata-reticularis (ZFR) cells in a dose-dependent manner. In order to study possible mechanisms, ZFR cells were incubated with S-petasin (10(-5) M) in the presence or absence of forskolin (adenylate cyclase activator, 10(-6) - 10(-4) M), 8-Br-cAMP (a cAMP analogue, 10(-6) 10(-4) M), 25-OH-cholesterol (pregnenolone biosynthesis precursor, 10(-5) M) combined with trilostane (a blocker of 3beta-hydroxysteriod dehydrogenase, 3beta-HSD, 10(-6) M) and deoxycorticosterone (corticosterone biosynthesis precursor, 10(-9) - 10(-6) M) at 37 degrees C for 1h. The concentration of pregnenolone and corticosterone in media were measured by radioimmunoassay. The stimulatory effects of corticosterone secretion induced by forskolin (10(-5) - 10(-4) M), 8-Br-cAMP (10(-5) - 10(-4) M) and deoxycorticosterone (10(-7) - 10(-6) M) were reduced by S-petasin at 10(-5) M. The stimulatory effects of pregnenolone secretion induced by 25-OH-cholesterol combined with or without trilostane was reduced by S-petasin at 10(-5) M. These results suggest that S-petasin inhibits the production of corticosterone from rat ZFR cells in part through decreasing the activities of adenylyl cyclase, P450scc and 11beta-hydroxylase.
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PMID:Effects of S-petasin on corticosterone release in rats. 1281 4

Hypersecretion of cortisol is associated with hypertension. In addition, an abnormal cortisol metabolism may play a role in the pathogenesis of hypertension. The 11beta-hydroxysteroid dehydrogenase (11beta-HSD) isozymes catalyze interconversion of cortisol and cortisone and play an important role in the regulation of the effects of cortisol. Activity of 11beta-HSD type 2, converting active cortisol in inactive cortisone, is crucial in preventing access of cortisol to the renal mineralocorticoid receptors (MRs). Decreased activity of this isozyme in the kidney, either congenitally in Apparent Mineralocorticoid Excess syndrome or acquired following licorice consumption, allows cortisol access to the MRs, resulting in hypokalemic hypertension. In normotensive subjects, an association has been demonstrated between blood pressure increase on a high-salt diet and a mild decrease of renal 11beta-HSD2 activity. In ectopic adrenocorticotropic hormone (ACTH), plasma cortisol levels are very high, resulting in mineralocorticoid hypertension caused by saturation of the available renal 11beta-HSD2 capacity. Activity of the 11beta-HSDs has also been demonstrated in many extrarenal sites. Several studies have demonstrated extrarenal effects of cortisol on blood pressure, as well as a possible role for altered extrarenal 11beta-HSD activities in the pathogenesis of hypertension. More studies are needed to clarify the role of 11beta-HSDs in the pathogenesis of hypertension.
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PMID:Cortisol, 11beta-hydroxysteroid dehydrogenases, and hypertension. 1547 32

The present study was performed to examine the role of the endogenous beta-endorphinergic system on blood pressure regulation, sympathetic and brain activity during body sodium overload. Beta-endorphin knockout (beta end-/-), heterozygous (beta end+/-) and wild-type (beta end+/+) mice were submitted for two weeks to either a normal- or a high-sodium diet (NSD and HSD, respectively), and systolic blood pressure (SBP), urinary catecholamines (as an index of sympathetic nervous system activity), and the brain pattern of Fos-like immunoreactivity (as a marker of neuronal activation) were evaluated in each group. HSD caused a significant increase in SBP in beta end-/- mutant mice compared with beta end+/+ mice kept in the same experimental conditions (P < 0.01), but no statistical differences were observed between beta end+/- and beta end+/+ on a HSD. Moreover, when animals from the three genetic lines were fed with a NSD no changes in SBP were evidenced. With regard to brain activity, beta end-/- mice maintained on a HSD showed a significant increase in Fos-like immunoreactive neurons in the median preoptic nucleus (P < 0.01) compared with beta end+/- and beta end+/+ animals. Additionally, beta end-/- mice had higher levels of urinary epinephrine excretion (P < 0.05) on a HSD in comparison to beta end+/+ and beta end+/- animals in the same experimental conditions. No differences, however, were registered in norepinephrine and dopamine urinary excretion in animals from the three genetic lines after two weeks on either a HSD or a NSD. In summary, our results indicate that the beta-endorphinergic system may play a part in the compensatory response to sodium overload, since the absence of beta-endorphin causes an increase in systolic blood pressure, and increases median preoptic nucleus neural activity and urinary epinephrine excretion.
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PMID:Beta-endorphin involvement in the regulatory response to body sodium overload. 1688 79


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