Adrenarche in Prader-Willi syndrome appears not related to insulin sensitivity and serum adiponectin

Prader-Willi syndrome (PWS) is a genetic disorder characterized by dysmorphic features, obesity, hypogonadism, hypotonia and mental retardation. Obesity has been linked to insulin resistance and the latter has also been associated with premature adrenarche. Since up to date a controlled study to investigate adrenarche and its hormonal regulation was lacking in PWS, our aim was to assess whether prepubertal PWS patients develop premature adrenarche and its relationship with markers of insulin sensitivity. Fourteen prepubertal children with PWS (6 M, 8 F) and 10 non-syndromal simple obese matched controls (5 M, 5 F) participated (mean age: 7.62 +/- 1.84 years). A fasting blood sample was obtained for adrenal and ovarian androgens, sex hormone binding globulin, insulin-like growth factor-I (IGF-I), insulin-like growth factor binding protein-1, leptin, adiponectin and a lipid profile. Thereafter an oral glucose tolerance test was performed. PWS patients were smaller at birth and a higher proportion displayed premature pubarche. No differences were found in testosterone, androstenedione, sex hormone binding globulin, free androgen index, homeostatic model assessment-IR, 2-hour insulin, leptin or adiponectin levels. 17-hydroxyprogesterone and DHEAS levels however, were significantly higher in PWS. IGF-I levels were significantly lower in PWS and correlated significantly with height SDS (p < 0.05). In conclusion, a higher proportion of premature adrenarche in our PW patients was observed, which was not explained by differences in insulin sensitivity or plasma levels of adipokines and IGF-I.     

Pronounced adrenarche and precocious pubarche in boys

In girls, pronounced adrenarche with precocious pubarche (PP) has been related to reduced fetal growth and to a cluster of endocrine-metabolic abnormalities. We examined whether these associations are also evident in boys with PP. The study population consisted of matched groups of boys (n = 58; age range 5-15 years) without or with a history of PP. After stratification for pubertal development, non-PP and PP boys displayed comparable results for the studied variables, including serum insulin-like growth factor I, sex hormone binding globulin, insulin-like growth factor binding proteins 1 and 3, indices of circulating glucose and insulin responsiveness to an oral glucose load, and birth weight SD score. In conclusion, the present results indicate that adrenarche-driven PP in boys is, in contrast to PP in girls, not associated with a cluster of endocrine-metabolic abnormalities and is not related to reduced fetal growth. These observations support the view that adrenarche-driven PP in boys may be regarded as a variant of normal development. Copyrightz1999S.KargerAG,Basel     

11beta-hydroxysteroid dehydrogenase type 1 deficiency ('apparent cortisone reductase deficiency') in a 6-year-old boy

OBJECTIVE: We present the 1st case of prepubertal hyperandrogenism because of a defect in the conversion of cortisone (E) to cortisol (F) by hepatic 11beta-hydroxysteroid dehydrogenase type 1. METHODS AND RESULTS: Clinical and anthropometric data were obtained. Serum androgens and gonadotropins with luteinizing hormone releasing hormone stimulation test, dexamethasone suppression test, and corticotropin-releasing hormone stimulation test were evaluated. Adrenal imaging and urinary steroid profiling by gas chromatography/mass spectrometry were employed. A 6.9-year-old boy presented with precocious pubarche, height (+2.6 SD), accelerated bone age (11.5 years), and Tanner stage 2 pubic hair and genitalia. Serum androgen levels were elevated and dexamethasone suppressible. Serum F was normal, but the E concentration was increased. Central precocious puberty and congenital adrenal hyperplasia were excluded. The excretion of androgen metabolites was moderately increased, but a highly increased tetrahydrocortisone (THE) and a diminished tetrahydrocortisol (THF + allo-THF) excretion was found with a [THF + allo-THF/ THE] ratio of 0.032 (normal controls 1.05 +/- 0.17). The corticotropin-releasing hormone stimulation test showed an exaggerated adrenocorticotropic hormone response, suggesting a relative deficiency of F. Two months of hydrocortisone treatment (17.5 mg daily) failed to suppress androgens adequately. Treatment with dexamethasone (0.375 mg/daily) resulted in androgen suppression. CONCLUSIONS: In the case of precocious pubarche and accelerated growth, the diagnosis of 11beta-hydroxysteroid dehydrogenase type 1 deficiency ('apparent cortisone reductase deficiency') should be considered. The diagnosis is based on determinations of urinary steroid metabolites.     

A cross-sectional study of dehydroepiandrosterone sulfate in prepubertal children with myelomeningocele

OBJECTIVE: To assess biochemical characteristics of adrenarche in patients with myelomeningocele (MMC), we examined serum levels of dehydroepiandrosterone sulfate (DHEAS) in prepubertal MMC patients. PATIENTS AND METHODS: The study included a total of 54 prepubertal patients with MMC and shunted hydrocephalus: 13 patients (2 m, 11 f; aged 4.6-10.1 years, mean 8.1 +/- 0.4) with isolated pubarche (Tanner stage PH 2-4, B1 or testes volume < or =3 ml) and 41 prepubertal MMC patients without pubarche (17 m, 24 f; aged 2.0-11.9 years; mean 6.8 +/- 2.5). DHEAS levels were measured directly by chemiluminescence immunoassay (Nichols, USA). Auxological data (supine length, body mass index (BMI), arm span) and bone age (BA) were recorded. RESULTS: (mean +/- SD): Basal DHEAS levels correlated with chronological age (CA) (r = 0.32, p < 0.05), BA (r = 0.65, p < 0.01; n = 23), BMI (r = 0.54, p < 0.01) and pubic hair stage (PH1 vs. PH2-4, r = 0.49, p < 0.01). 10/11 patients aged 2-4 years had DHEAS levels in the normal range, whereas 18/40 (45.0%) of the 5- to 9-year-old patients showed elevated levels (>+2 SDS). Ten patients with isolated pubarche (10/13; 2 m, 8 f; CA 8.3 +/- 1.5 years) and 9 patients without pubarche (9/41; 6 m, 3 f; CA 6.9 +/- 2.1 years) had elevated DHEAS levels (+6.34 and +4.05 SDS, respectively). The values correlated with BA/CA ratio (p < 0.05, n = 23). There was a trend to higher BMI SDS levels in patients with elevated DHEAS levels. CONCLUSION: Our data show an early and increased activation of adrenal androgen secretion in MMC patients.     

MC4R、POU1F1基因对京海黄鸡生长性能的遗传效应

以MC4R和POU1F1基因为候选基因, 采用PCR-SSCP和DNA测序技术检测两个候选基因在京海黄鸡群体中的单核苷酸多态性(SNPs), 同时对候选基因与京海黄鸡生长性能的相关性进行了研究。结果表明, MC4R基因编码区第662 bp位置有G→C碱基的点突变, 在京海黄鸡中检测到AA、AB、BB 3种基因型, A等位基因频率为0.929, B等位基因频率为0.071; 在POU1F1基因exon3在序列的第5 231 bp位置有一个A→T碱基的点突变, 检测到CC、CD、DD 3种基因型, C等位基因频率为0.500, D等位基因频率为0.500。采用GLM模型分析基因型对生长性能的遗传效应, 结果表明, MC4R基因AA基因型个体的4、8、12周龄体重显著地高于BB型个体(P<0.05), 16周龄体重差异极显著(P<0.01); POU1F1基因CD基因型个体体重极显著高于CC型和DD型(P<0.01)。因此推测MC4R和POU1F1基因可能是影响鸡生长性状的主效基因或与主效基因紧密连锁的标记基因, 能够在分子标记辅助选择中用于对鸡生长性状的遗传改良。     

POU1F1-mediated activation of hGH-N by deoxyribonuclease I hypersensitive site II of the human growth hormone locus control region

The human growth hormone gene (hGH-N) is regulated by a distal locus control region (LCR) composed of five deoxyribonuclease I hypersensitive sites (HSs). The region encompassing HSI and HSII contains the predominant pituitary somatotrope-specific hGH-N activation function of the LCR. This activity was attributed primarily to POU1F1 (Pit-1) elements at HSI, as linkage to HSI was sufficient for properly regulated hGH-N expression in transgenic mice, while HSII alone had no activity. However, the presence of HSII in conjunction with HSI further enhanced hGH-N transgene expression, indicating additional determinants of pituitary hGH-N activation in the HSII region, but limitations of transgenic models and previous ex vivo systems have prevented the characterization of HSII. In the present study, we employ a novel minichromosome model of the hGH-N regulatory domain and show that HSII confers robust POU1F1-dependent activation of hGH-N in this system. This effect was accompanied by POU1F1-dependent histone acetylation and methylation throughout the minichromosome LCR/hGH-N domain. A series of in vitro DNA binding experiments revealed that POU1F1 binds to multiple sites at HSII, consistent with a direct role in HSII function. Remarkably, POU1F1 binding was localized in part to the 3' untranslated region of a primate-specific LINE-1 (long interspersed nuclear element 1) retrotransposon, suggesting that its insertion during primate evolution may have conferred function to the HSII region in the context of pituitary GH gene regulation. These observations clarify the function of HSII, expanding the role of POU1F1 in hGH LCR activity, and provide insight on the molecular evolution of the LCR.     

Long non-coding RNA POU6F2-AS2 promotes cell proliferation and drug resistance in colon cancer by regulating miR-377/BRD4

The aim of this study was to explore the molecular mechanism of lncRNA POU6F2-AS2 in proliferation and drug resistance of colon cancer. Total paired 70 colon cancer and adjacent normal tissues were collected from colon cancer patients. Colon cancer and normal colonic epithelial cells were purchased. POU6F2-AS2 was up- or down-expressed by vectors. LC50 of all cell lines before and after transfection with these plasmids was detected. qRT-PCR was used to detect the expression of POU6F2-AS2, miR-377 and BRD4 before or after transfection. In situ hybridization was also undertaken to detect the level of POU6F2-AS2. Different concentrations of 5-Fu (0, 1, 2.5, 5, 10, 20, 40 and 80 μg/mL) were used for 5-FU insensitivity assay. CCK-8 and crystal violet staining assay were used for detecting cell proliferation, and flow cytometry was used for identifying cell cycle distribution and apoptosis. In order to detect the fragmented DNA in apoptotic cells, TUNEL assay was used. RNA pull-down assay and luciferase reporter assay were used to verify the binding site. Rescue assay confirmed the subtractive effect of miR-377 inhibitors. POU6F2-AS2 was highly expressed in colon cancer, which was associated with clinical pathology. Up-regulated POU6F2-AS2 promoted cell proliferation and cell cycle of colon cancer cells. Overexpression of POU6F2-AS2 inhibited the expression of miR-377 and then up-regulated the expression of BRD4. Up-regulated BRD4 ultimately promoted cell proliferation and cell survival Down-regulated POU6F2-AS2 showed enhanced sensitivity of 5-FU. POU6F2-AS2 promoted cell proliferation and drug resistance in colon cancer by regulating miR-377/BRD4 gene.     

Hormones and behavior of prepubertal and peripubertal chimpanzees

Twenty-one chimpanzees ranging in age from 2.9 to 9.2 years at the midpoint of a study consisting of five 4-week blocks were studied behaviorally in four groups of five or six animals per group, balanced for age and sex. Blood samples for radioimmunoassay of follicle-stimulating hormone (FSH), luteinizing hormone, 17 beta-estradiol, testosterone, dehydroepiandrosterone (DHA), DHA sulfate (DHAS), and cortisol were obtained once each 4-week block. Sex differences were found only in the categories of play duration and initiative and genital inspection, all of which were greater for the males. Several categories (6) of play and other affiliative behaviors were negatively correlated with age and/or body weight for the males, whereas fewer of those categories (2) were so correlated in the females. Hierarchical behavior, genital inspection, solitary behavior other than play, and autogrooming were all positively correlated with age and/or body weight for the males, and only autogrooming for the females. FSH and testosterone levels and testicular volume were positively correlated with age and body weight in the males, whereas for the females cortisol was negatively correlated with body weight and only FSH and the ratios of DHA and DHAS to cortisol were positively correlated with age and/or body weight. Most of the behaviors that were significantly correlated with age and body weight for the males were also correlated in the same direction with FSH and testosterone levels and testicular volume, but not with DHA or DHAS levels. The data are consistent with the view that testosterone, but not the adrenal androgens DHA and DHAS, contributed to the behavioral development of the males. There were few significant correlations between hormones and behavior for the females and interpretation is not clear. The absence of age-related increases in DHA and DHAS of both the males and females, in contrast to the pattern of FSH (and testosterone for the males), supports the growing consensus that adrenarche and puberty are independent developmental processes. The absence of any strong correlations between behavior and levels of the adrenal androgens in either the males or females suggests that adrenarche per se is not a significant event in the behavioral development of chimpanzees.     

Long noncoding RNA POU6F2-AS1 regulates lung cancer aggressiveness through sponging miR-34c-5p to modulate KCNJ4 expression

It has been extensively reported that long noncoding RNAs (lncRNAs) were closely associated with multiple malignancies. The aim of our study was to investigate the effects and mechanism of lncRNA POU6F2-AS1 in lung adenocarcinoma (LADC).The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets provided us the information of LADC clinical samples. High-regulation of POU6F2-AS1 was presented in LADC tissues compared with adjacent normal tissues, which was correlated with poor outcome of LADC patients. Functional experiments in Calu-3 and NCI-H460 cells showed that POU6F2-AS1 significantly promoted LADC cell proliferation, colony formation, invasion and migration. Moreover, through online prediction, luciferase reporter assay and Pearson’s correlation analysis, we found that POU6F2-AS1 may act as a competing endogenous RNA (ceRNA) of miR-34c-5p and facilitated the expression of potassium voltage-gated channel subfamily J member 4 (KCNJ4). The promoting effect of cell aggressiveness induced by POU6F2-AS1 was enhanced by KCNJ4, whilst was abrogated due to the overexpression of miR-34c-5p. Collectively, POU6F2-AS1 might function as a ceRNA through sponging miR-34c-5p to high-regulate KCNJ4 in LADC, which indicates that POU6F2-AS1 might be a promising therapeutic target with significant prognostic value for LADC treatment.     

Long noncoding RNA POU3F3 promotes cancer cell proliferation in prostate carcinoma by upregulating rho-associated protein kinase 1

Long noncoding RNAs (lncRNAs) POU3F3 is overexpressed in esophageal squamous-cell carcinomas, while its role in other human cancers is unclear. In this study we found that POU3F3 and rho-associated protein kinase 1 (ROCK1) were both increased in tumor tissues than in adjacent healthy tissues of patients with prostate carcinoma. Expression levels of POU3F3 increased with increase in the diameter of tumor but were not significantly affected by lymph node metastasis or distant metastasis. Expression levels of POU3F3 and ROCK1 were positive correlated in tumor tissues but not in adjacent healthy tissues. POU3F3 and ROCK1 overexpression promoted, while ROCK1 knockdown inhibited the proliferation of prostate carcinoma cells. ROCK1 knockdown reduced the enhancing effect of POU3F3 overexpression on cancer cell proliferation. POU3F3 overexpression led to ROCK1 overexpression in prostate carcinoma cells, while ROCK1 overexpression did not significantly affect POU3F3 expression. Therefore, lncRNA POU3F3 may promote cancer cell proliferation in prostate carcinoma by upregulating ROCK1.     

猪POU1F1基因部分序列变异和同源性分析

对长白、杜洛克、约克夏、姜曲海、梅山和香猪等六个猪种的POU1F1基因第四、第五和第六外显子分别进行PCR扩增,并对含有第四、第六外显子的PCR产物和含有第五外显子的克隆产物进行测序。结果表明：六个猪种中,POU1F1基因的第四外显子存在碱基突变,为T→C。对该序列进行Nla Ⅲ 酶消化,产生两种不同的基因型(GG和HH);而第五和第六外显子则高度保守,未发现任何突变。将人POU1F1基因第四外显子、POU同源区核苷酸编码序列和氨基酸序列,分别与猪、小鼠、牛的POU1F1基因相应的核苷酸序列和氨基酸序列进行同源性比较,结果发现：人与猪、小鼠、牛的POU1F1基因第四外显子的核苷酸同源性分别高达93.9%、86.7%、92.1%,而由第四外显子编码的部分POU特异区的氨基酸序列则完全一致;人与猪、小鼠、牛POU同源区的核苷酸同源性分别为91.4%、85.1%、87.9%,氨基酸同源性分别为96.6%、94.8%、90.2%。这说明在哺乳动物中,其POU1F1蛋白的POU同源区和由第四外显子编码的POU特异区部分是高度保守的;猪可作为实验动物,建立人类相关疾病模型,为医学研究提供参考依据。