bluuebunny/crossref_metadata_2025_split huggingface dataset:
Atrial Natriuretic Peptide Promotes Pancreatic Islet β-Cell Growth and Akt/Foxo1a/Cyclin D2 Signaling
Authors: You Hui , Laychock Suzanne G. 
Published: October 2009

Abstract
The adult differentiated insulin-secreting pancreatic islet β-cell experiences slow growth. This study shows that atrial natriuretic peptide (ANP) stimulates cell proliferation and [3H]thymidine incorporation in INS-1E glucose-sensitive rat β-cell line cells and isolated rat islet DNA. In addition, cGMP, the second messenger of natriuretic peptide receptors (NPR) A and B, stimulated islet DNA biosynthesis. The NPR-A receptor was expressed in INS-1E cells and islets. ANP-stimulated INS-1E cell DNA biosynthesis was blocked by preincubation with LY294002 (50 μm), an inhibitor of phosphatidylinositol 3′-kinase (PI3K). An indicator of cell cycle progression, cyclin D2 mRNA was increased by 2- to 3-fold in ANP- or 8-Br-cGMP-treated INS-1E cells and islets, and these responses were inhibited by LY294002. ANP and 8-Br-cGMP stimulated the phosphorylation of Akt and Foxo1a in INS-1E cells and islets, and LY294002 inhibited these responses. In contrast, ANP reduced the levels of phospho-ERK in INS-1E cells. Pancreas duodenum homeobox-1 (PDX-1) is essential for pancreas development, insulin production, and glucose homeostasis, and ANP increased PDX-1 mRNA levels by 2- to 3-fold in INS-1E cells and islets. The levels of glucokinase mRNA in islets and INS-1E cells were also increased in response to ANP. The evidence suggests that pancreatic β-cell NPR-A stimulation results in activation of a growth-promoting signaling pathway that includes PI3K/Akt/Foxo1a/cyclin D2. These data support the conclusion that the activation of Akt by ANP or 8-Br-cGMP promotes cyclin D2, PDX-1, and glucokinase transcription by phosphorylating and restricting Foxo1a activity.
Expression of Guanylyl Cyclase (GC)-A and GC-B during Brain Development: Evidence for a Role of GC-B in Perinatal Neurogenesis
Authors: Müller Dieter , Hida Balanes , Guidone Gabriela , Speth Robert C. , Michurina Tatyana V. , Enikolopov Grigori , Middendorff Ralf 
Published: October 2009

AbstractAtrial (ANP) and C-type (CNP) natriuretic peptide generate physiological effects via selective activation of two closely related membrane receptors with guanylyl cyclase (GC) activity, known as GC-A and GC-B. As yet, however, the discrete roles for ANP/GC-A vs. CNP/GC-B signaling in many mammalian tissues are still poorly understood. We here used receptor affinity labeling and GC assays to characterize comparatively GC-A/GC-B expression and functional activity during rat brain development. The study revealed that GC-B predominates in the developing and GC-A in the adult brain, with regional differences each between cerebral cortex, cerebellum, and brain stem. Whereas GC-A levels nearly continuously increase between embryonal d 18 and adult, GC-B expression in brain is highest and widely distributed around postnatal d 1. The striking perinatal GC-B peak coincides with elevated expression of nestin, a marker protein for neural stem/progenitor cells. Immunohistochemical investigations revealed a cell body-restricted subcellular localization of GC-B and perinatal abundance of GC-B-expressing cells in regions high in nestin-expressing cells. However, and supported by examination of nestin-GFP transgenic mice, GC-B and nestin are not coexpressed in the same cells. Rather, GC-B+ cells are distinguished by expression of NeuN, an early marker of differentiating neurons. These findings suggest that GC-B+ cells represent neuronal fate-specific progeny of nestin+ progenitors and raise the attention to specific and pronounced activities of CNP/GC-B signaling during perinatal brain maturation. The absence of this activity may cause the neurological disorders observed in GC-B-deficient mice.
Brain-Endocrine Interactions: A Microvascular Route in the Mediobasal Hypothalamus
Authors: Ciofi Philippe , Garret Maurice , Lapirot Olivier , Lafon Pierrette , Loyens Anne , Prévot Vincent , Levine Jon E. 
Published: October 2009

Abstract
Blood-borne hormones acting in the mediobasal hypothalamus, like those controlling food intake, require relatively direct access to target chemosensory neurons of the arcuate nucleus (ARC). An anatomical substrate for this is a permeable microvasculature with fenestrated endothelial cells in the ARC, a system that has awaited comprehensive documentation. Here, the immunofluorescent detection of endothelial fenestral diaphragms in the rat ARC allowed us to quantitate permeable microvessels throughout its rostrocaudal extent. We have determined that permeable microvessels are part of the subependymal plexus irrigating exclusively the ventromedial (vm) ARC from the subadjacent neuroendocrine median eminence. Unexpectedly, permeable microvessels were concentrated proximal to the pituitary stalk. This marked topography strongly supports the functional importance of retrograde blood flow from the pituitary to the vmARC, therefore making a functional relationship between peripheral long-loop, pituitary short-loop, and neuroendocrine ultra-short loop feedback, altogether converging for integration in the vmARC (formerly known as the hypophysiotrophic area), thereby so pivotal as a multicompetent brain endocrinostat.
Forkhead Box O1/Pancreatic and Duodenal Homeobox 1 Intracellular Translocation Is Regulated by c-Jun N-Terminal Kinase and Involved in Prostaglandin E2-Induced Pancreatic β-Cell Dysfunction
Authors: Meng Zhuoxian , Lv Jinghuan , Luo Ying , Lin Yan , Zhu Yunxia , Nie Jia , Yang Tao , Sun Yujie , Han Xiao 
Published: October 2009

Abstract
Prostaglandin E2 (PGE2) is a well-known mediator of β-cell dysfunction in both type 1 and type 2 diabetes. We recently reported that down-regulation of the Akt pathway activity is implicated in PGE2-induced pancreatic β-cell dysfunction. The aim of this study was to further dissect the signaling pathway of this process in pancreatic β-cell line HIT-T15 cells and primary mouse islets. We found that PGE2 time-dependently increased the c-Jun N-terminal kinase (JNK) pathway activity. JNK inhibition by the JNK-specific inhibitor SP600125 reversed PGE2-inhibited glucose-stimulated insulin secretion (GSIS). PGE2 induced dephosphorylation of Akt and FOXO1, leading to nuclear localization and transactivation of FOXO1. Activation of FOXO1 induced nuclear exclusion but had no obvious effect on the whole-cell protein level of pancreatic and duodenal homeobox 1 (PDX1). However, these effects were all attenuated by JNK inhibition. Furthermore, adenovirus-mediated overexpression of dominant-negative (DN)-FOXO1 abolished whereas constitutively active (CA)-FOXO1 mimicked the effects of PGE2 on GSIS in isolated mouse islets. In addition, we demonstrated that DN-JNK1 but not DN-JNK2 or CA-Akt abolished the PGE2-induced AP-1 luciferase reporter activity, whereas DN-JNK1 and CA-Akt but not DN-JNK2 reversed the effect of PGE2 on FOXO1 transcriptional activity, and overexpression of DN-JNK1 rescued PGE2-impaired GSIS in mouse islets. Our results revealed that activation of the JNK is involved in PGE2-induced β-cell dysfunction. PGE2-mediated JNK1 activation, through dephosphorylation of Akt and FOXO1, leads to nuclear accumulation of FOXO1 and nucleocytoplasmic shuttling of PDX1, finally resulting in defective GSIS in pancreatic β-cells.
Skeletal Muscle Lipogenic Protein Expression Is Not Different between Lean and Obese Individuals: A Potential Factor in Ceramide Accumulation
Authors: Thrush A. Brianne , Brindley David N. , Chabowski Adrian , Heigenhauser George J. , Dyck David J. 
Published: October 2009

Context: Skeletal muscle lipid content is increased in obesity. Recent evidence suggests that fatty acid (FA) storage as triacylglycerol (TAG) represents a metabolically safe pool compared to the more bioactive diacylglycerol (DAG) and ceramide.Objective/Design: The purpose of this study was to compare the expression of lipogenic proteins and ceramide and DAG content in skeletal muscle of lean and obese humans. We hypothesized that lipogenic protein expression would be increased in obese to facilitate the storage of excess FA as TAG.Participants: Eighteen lean (BMI ≤26 kg/m2) and 15 obese (BMI &gt;29 kg/m2) women participated in this study.Results: There was no difference in the expression of any lipogenic (stearoyl-CoA desaturase-1, stearoyl retinol binding protein-1c, mitochondrial glycerol-3-phosphate acyltransferase, diacylglycerol acyltransferase-1) or sphingolipid proteins measured between lean and obese humans. Total ceramide was increased in muscle from obese humans (lean vs. obese, 529.4 ± 54.8 vs. 672.4 ± 57.4 nmol/g; P &lt; 0.05), but there was no difference in total DAG content (lean vs. obese, 2244.1 ± 278.2 vs. 1941.4 ± 165.0 nmol/g). Content of protein phosphatase 2A, a ceramide target, was increased in muscle of obese humans (P &lt; 0.05).Conclusions: We propose that in muscle of obese humans there is an insufficient lipogenic response to the lipid oversupply, allowing more FA to be stored as reactive lipid species, particularly ceramide, potentially contributing to subsequent metabolic complications.
The Stability of Metabolic Syndrome in Children and Adolescents
Authors: Gustafson Jennifer K. , Yanoff Lisa B. , Easter Benjamin D. , Brady Sheila M. , Keil Margaret F. , Roberts Mary D. , Sebring Nancy G. , Han Joan C. , Yanovski Susan Z. , Hubbard Van S. , Yanovski Jack A. 
Published: October 2009

Context: Some studies suggest the presence of metabolic syndrome before adulthood may identify those at high risk for later cardiovascular morbidity, but there are few data examining the reliability of pediatric metabolic syndrome.
Objective: To examine the short- and long-term stability of pediatric metabolic syndrome.
Design: Metabolic syndrome was defined as having at least three of the following: waist circumference, blood pressure, and fasting serum triglycerides in the 90th or higher percentile for age/sex; high-density lipoprotein-cholesterol 10th or lower percentile for age/sex; and fasting serum glucose of at least 100 mg/dl. Short-term metabolic syndrome stability (repeated measurements within 60 d) was assessed in obese youth ages 6–17 yr. Long-term metabolic syndrome stability (repeated measurements more than 1.5 yr apart) was studied in 146 obese and nonobese children age 6–12 yr at baseline.
Patients and Setting: Convenience samples of obese and nonobese youth ages 6–17 yr participating in research studies were collected at a clinical research hospital.
Results: Short-term metabolic syndrome stability (repeat measurements performed 19.7 ± 13.1 d apart) was assessed in 220 children. The diagnosis of metabolic syndrome was unstable in 31.6% of cases. At their short-term follow-up visit, incidence of metabolic syndrome among participants who did not have metabolic syndrome at baseline was 24%. In the long term (repeat measurements performed 5.6 ± 1.9 yr apart), the diagnosis of metabolic syndrome was unstable in 45.5% of cases.
Conclusions: Cutoff-point-based definitions for pediatric metabolic syndrome have substantial instability in the short and long term. The value of making a cutoff-point-based diagnosis of metabolic syndrome during childhood or adolescence remains in question.
Six New Mutations of the Thyroglobulin Gene Discovered in Taiwanese Children Presenting with Thyroid Dyshormonogenesis
Authors: Niu Dau-Ming , Hsu Ju-Hui , Chong Kah-Wai , Huang Cheng-Hung , Lu Yung-Hsiu , Kao Chuan-Hong , Yu Hsiao-Chi , Lo Ming-Yu , Jap Tjin-Shing 
Published: October 2009

Background: Thyroglobulin (TG) defect is a rare cause of congenital hypothyroidism. Although only 44 mutations of the human TG gene have been identified, we have suspected a TG defect in 38% of Taiwan Chinese children/adolescents presenting with moderate or severe thyroidal dyshormonogenesis.Study Objective: The aim of the study is to report the discovery of new TG gene mutations and associated clinical manifestations of the defective TG protein.Patients and Results: In seven patients from six families, we detected six new TG gene mutations, including c.1348delT, p.R432X (c.1351C&gt;T), g.IVS3 + 2T&gt;G, c.1712delT, p.Q1765X (c.5350C&gt;T), and c.6047delA. The c.1348delT and p.R432X mutations were the most common, detected in 33 and 25%, respectively, of alleles studied. Haplotype analysis suggested that the c.1348delT and g.IVS3 + 2T&gt;G mutations are due to founder effects, whereas p.R432X is probably due to independently recurrent de novo mutations. mRNA transcript of the g.IVS3 + 2T&gt;G mutant, detected in whole blood by reverse transcription-nested PCR, showed skipping of exon 3 (98-bp deletion) and a frameshift, with a terminal signal after 17 altered amino acid residues.Conclusions: TG defects have an important role in severe thyroidal dyshormonogenesis (pretreatment, or after a 3-wk T4 withdrawal, plasma T4 ≦ 30 nmol/liter) in Taiwanese. Its genetic characteristics are markedly different from those described in other populations presenting with mutations of the TG gene.
Expression of Progesterone Receptor A form and Its Role in the Interaction of Progesterone with Cortisol on Cyclooxygenase-2 Expression in Amnionic Fibroblasts
Authors: Guo C. M. , Zhu X. O. , Ni X. T. , Yang Z. , Myatt L. , Sun K. 
Published: October 2009

Context: Human amnion fibroblasts produce abundant prostaglandins toward the end of gestation, which is believed to be one of the major events leading to parturition. Glucocorticoids have been shown to up-regulate cyclooxygenase-2 (COX-2) expression, the crucial enzyme catalyzing prostaglandin synthesis, in human amnion fibroblasts. Although a major propregnancy hormone, the effect of progesterone and the associated progesterone receptor subtypes in the regulation of both basal and glucocorticoid-induced COX-2 expression in human amnion fibroblasts have not been resolved.Methods and Results: Cultured human amnion fibroblasts prepared from the fetal membranes at term pregnancy without labor mainly expressed the progesterone receptor A form (PRA). Inhibition of endogenous progesterone production with trilostane or knockdown of PRA expression with small interfering RNA significantly enhanced the glucocorticoid receptor (GR)-mediated COX-2 induction by cortisol, whereas overexpression of PRA attenuated the induction by cortisol. Co-immunoprecipitation assay revealed PRA in the GR protein complex. Although exogenous progesterone did not alter COX-2 expression under basal conditions, it attenuated cortisol-induced COX-2 expression at concentrations about 10- to 50-fold higher, which might be achieved by competition with cortisol for GR.Conclusions: We demonstrated in this study that endogenous progesterone might counteract the induction of prostaglandin synthesis by cortisol via PRA transdominant repression of GR function, whereas high levels of progesterone might further inhibit the induction by cortisol via competitive binding to GR in human amnion fibroblasts. These inhibitory actions of progesterone and PRA on glucocorticoids and GR may partly explain the inconsistent effects of glucocorticoids on parturition in humans.
Human Adipose Tissue Macrophages: M1 and M2 Cell Surface Markers in Subcutaneous and Omental Depots and after Weight Loss
Authors: Aron-Wisnewsky Judith , Tordjman Joan , Poitou Christine , Darakhshan Froogh , Hugol Danielle , Basdevant Arnaud , Aissat Abdelhalim , Guerre-Millo Michèle , Clément Karine 
Published: October 2009

Context: Macrophages accumulate in adipose tissue and possibly participate in metabolic complications in obesity. Macrophage number varies with adipose tissue site and weight loss, but whether this is accompanied by phenotypic changes is unknown.
Objective: The objective of the study was to characterize the activation state of adipose tissue macrophages in human obesity.
Design/Setting: We performed a single-center prospective study.
Participants/Interventions: Paired biopsies of sc and omental adipose tissue were obtained during gastric surgery in 16 premenopausal obese women (aged 41.1 ± 8.6 yr; body mass index 43.8 ± 3.4 kg/m2). Subcutaneous adipose tissue biopsies were obtained 3 months later in obese subjects and in 10 nonobese women (aged 43.3 ± 3.5 yr; body mass index 22.5 ± 0.75 kg/m2). The number of macrophages stained with CD40, CD206, and CD163 surface markers was determined by immunochemistry.
Main Outcomes: The number of CD40+ macrophages significantly increased with obesity and in omental vs. sc adipose tissue in obese women. No significant changes in CD163+ and CD206+ macrophage counts was found with obesity and fat pad anatomical location. Three months after gastric surgery, the ratio of CD40+ to CD206+ macrophages was 2-fold lower than before surgery in the sc adipose tissue of obese subjects (P &lt; 0.001) due to a concomitant decrease of CD40+ and increase of CD206+ macrophages counts.
Conclusion: We suggest that the activation state of adipose tissue macrophages is weighted toward M1 over M2 status in obese subjects and switch to a less proinflammatory profile 3 months after gastric bypass.
Immunohistochemistry analyses suggest that gastric surgery switches the activation state of adipose tissue macrophages towards a M2-oriented, less pro-inflammatory phenotype in morbidly obese subjects.
Influence of Preterm Birth and Birth Size on Gonadal Function in Young Men
Authors: Kerkhof Gerthe F. , Leunissen Ralph W. J. , Willemsen Ruben H. , de Jong Frank H. , Stijnen Theo , Hokken-Koelega Anita C. S. 
Published: October 2009

Background/Objectives: Preterm birth has been associated with reduced reproduction rates and being born small for gestational age (SGA) with reduced gonadal function. We hypothesized that alterations concerning gonadal function in young men are not due to preterm birth or being born SGA, but are due to other (environmental) factors.
Methods: In 207 young men of the PROGRAM/PREMS cohort study, aged 18–24 yr, the influence of preterm birth, birth length, and birth weight on serum levels of anti-Mullerian hormone, inhibin B, testosterone, SHBG, non-SHBG-bound testosterone, LH, and FSH was analyzed with multiple regression modeling. In addition, markers of male gonadal function were analyzed in four subgroups: men born SGA with either short stature or catch-up growth, or men born appropriate for gestational age with idiopathic short stature or with normal stature (control).
Results: Preterm birth and SGA did not affect gonadal function. After adjustment for age, birth size, adult height, fat mass, and socioeconomic status (SES), preterm birth even showed a positive relation with inhibin B. Higher SES was associated with higher inhibin B levels. Higher fat mass was associated with decreased testosterone and SHBG levels and maternal smoking with increased LH and non-SHBG-bound testosterone levels. After adjustment for confounders, there were no significant differences in gonadal function between the subgroups.
Conclusion: Preterm birth and SGA did not affect gonadal function in young men. Factors that affected gonadal function were: lower SES, a higher fat mass, and maternal smoking during pregnancy.
Preterm birth and small birth size for gestational age do not affect male gonadal function in early adulthood.
Activating Autoantibodies against the Calcium-Sensing Receptor Detected in Two Patients with Autoimmune Polyendocrine Syndrome Type 1
Authors: Kemp E. Helen , Gavalas Nikos G. , Krohn Kai J. E. , Brown Edward M. , Watson Philip F. , Weetman Anthony P. 
Published: October 2009

Context: Autoimmune polyendocrine syndrome type 1 (APS1) is an autosomal recessive disorder caused by mutations in the autoimmune regulator (AIRE) gene. Hypoparathyroidism occurs in 80% of patients with APS1 and has been suggested to result from an autoimmune reaction against the calcium-sensing receptor (CaSR) in parathyroid cells. Anti-CaSR binding antibodies have previously been detected in patients with APS1.
Objective: The aim of this study was to determine whether anti-CaSR antibodies present in APS1 patients could modulate the response of the CaSR to stimulation by Ca2+.
Results: The results indicated that two of the 14 APS1 patients included in the study had anti-CaSR antibodies that stimulated the receptor. These antibodies were detected by their ability to increase both Ca2+-dependent extracellular signal-regulated kinase phosphorylation and inositol phosphate accumulation in human embryonic kidney 293 cells expressing the CaSR.
Conclusion: An important implication of the present results is that although the majority of APS1 patients do not have CaSR-stimulating antibodies, there may be a small but substantial minority of patients in whom the hypoparathyroid state is the result of functional suppression of the parathyroid glands rather than their irreversible destruction.
High Prevalence of Metabolic Syndrome in First-Degree Male Relatives of Women with Polycystic Ovary Syndrome Is Related to High Rates of Obesity
Authors: Coviello Andrea D. , Sam Susan , Legro Richard S. , Dunaif Andrea 
Published: October 2009

Context: Women with polycystic ovary syndrome (PCOS) have twice the risk for metabolic syndrome (MetS) compared to women from the general population. Mothers and sisters of affected women also have an increased prevalence of MetS.
Objective: The aim of the study was to determine the prevalence of MetS in fathers and brothers of women with PCOS compared to men from the general population.
Design and Setting: We conducted a cross-sectional observational study at academic medical centers.
Participants: A total of 211 fathers and 58 brothers of women with PCOS were studied and compared to 1153 and 582 Third National Health and Nutrition Survey (NHANES III) men of similar age and race/ethnicity, respectively.
Main Outcome Measure: We measured MetS prevalence.
Results: The prevalence of MetS was increased in fathers (42 vs. 32%; P = 0.006) and brothers (22 vs. 9%; P = 0.001) compared to NHANES III men. Fathers and brothers had higher body mass index (BMI) than NHANES III men (P &lt; 0.0001). MetS rates were similar in fathers and brothers compared to NHANES III groups after adjusting for BMI. Total testosterone was inversely related to MetS in both fathers and brothers, but this relationship was also accounted for by the higher BMI in male relatives.
Conclusion: Male relatives of women with PCOS had increased prevalence rates of MetS and obesity compared to the general U.S. male population from NHANES III. In contrast to women with PCOS and their female relatives, the higher prevalence of MetS in male relatives was accounted for by elevated BMI. These findings suggest that the high rates of MetS in male relatives of women with PCOS are related to higher rates of obesity than the general population.
The high prevalence of metabolic syndrome in first degree male relatives of women affected by PCOS compared to similar men in the NHANES III population is attributable to higher rates of obesity than the general population.