bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mineralocorticoid Action and Sodium-Hydrogen Exchange: Studies in Experimental Cardiac Fibrosis
Authors: Young Morag , Funder John 
Published: June 2003

Abstract
There is increasing evidence that the trigger for cardiac fibrosis in response to mineralocorticoid/salt administration is coronary vasculitis and that effects can be seen within days of deoxycorticosterone acetate (DOCA) administration. Furthermore, rapid, nongenomic mineralocorticoid effects on the sodium-hydrogen exchanger (NHE-1) in vascular smooth muscle cells have recently been described. That this mechanism may act as an inflammatory or profibrotic signal was tested by comparing the specific NHE-1 antagonist cariporide and the mineralocorticoid receptor antagonist K canrenoate in the rat model of mineralocorticoid/salt perivascular fibrosis over 8 d of DOCA/salt administration. Interstitial collagen, inflammatory cell infiltration, and inflammatory markers were determined. DOCA elevated blood pressure above control, cariporide +DOCA, or K canrenoate +DOCA rats, without cardiac hypertrophy. At 8 d interstitial collagen was significantly elevated in the DOCA-alone group, with levels in cariporide- and K canrenoate-treated rats not different from control. Expression of osteopontin, cyclooxygenase-2, and ED-1 were elevated by DOCA treatment, blocked by potassium canrenoate, and (for ED-1 and osteopontin) partially reduced by cariporide. These results suggest mineralocorticoid/salt-induced cardiac fibrosis may involve coronary vascular smooth muscle cell NHE-1 activity as a possible contributor to the cascade of transcriptional events that produce the characteristic coronary vasculitis seen with excess mineralocorticoid and salt.
Inhibition of the Stem Cell Factor-Induced Migration of Mast Cells by Dexamethasone
Authors: Jeong Hyun-Ja , Na Ho-Jeong , Hong Seung-Heon , Kim Hyung-Min 
Published: June 2003

AbstractMast cell accumulation can be causally related to several allergic inflammations. Previous work has demonstrated that glucocorticoids decreased tissue mast cell number, and stem cell factor (SCF)-induced migration of mast cells required p38 MAPK activation. In the present study we investigated the effects of dexamethasone on SCF-induced migration of rat peritoneal mast cells (RPMCs). SCF significantly induced the migration of RPMCs at 4 h. Dexamethasone dose-dependently inhibited SCF-induced migration of RPMCs (∼90.1% at 100 nm; P &lt; 0.05). The MAPK p38 inhibitor SB203580 (20 μm) also inhibited the SCF-induced migration. The ability of SCF to enhance morphological alteration and filamentous actin formation was also abolished by treatment with dexamethasone. Dexamethasone inhibited SCF-induced p38 MAPK activation to near-basal levels and induced MAPK phosphatase-1 expression. In addition, SCF-induced inflammatory cytokine production was significantly inhibited by treatment with dexamethasone or SB203580 (P &lt; 0.01). Our results show that dexamethasone potently regulates SCF-induced migration, p38 MAPK activation, and inflammatory cytokine production through the expression of MKP-1 protein in RPMCs. Such modulation may have functional consequences during dexamethasone treatment, especially mast cell-mediated allergic inflammation disorders.
Thyroid Hormones Interact with Glucocorticoids to Affect Somatotroph Abundance in Chicken Embryonic Pituitary Cells in Vitro
Authors: Liu Lixin , Dean Carlton E. , Porter Tom E. 
Published: June 2003

AbstractOur laboratory has reported that somatotroph differentiation occurs between d 14 and d 16 of chicken embryonic development and that corticosterone (CORT) can induce somatotroph differentiation at an earlier age in vitro and in vivo. The objective of the present study was to test for thyroid hormone-CORT interactions on somatotroph differentiation in vitro. Pituitary cells from d 11 chicken embryos were treated with CORT and thyroid hormones, and GH-producing somatotrophs were detected by reverse hemolytic plaque assays and immunocytochemistry. We found that thyroid hormones can act synergistically with CORT to further augment the abundance of somatotrophs in vitro but have little to no effect on their own. Both T4 and T3 could act synergistically with CORT to increase somatotroph abundance, but the effects of T3 were biphasic, inhibiting CORT actions at higher concentrations. The monodeiodination inhibitor iopanoic acid inhibited the synergistic effect of T4 on CORT induction of GH cells in vitro but not the synergistic effect of CORT and T3 or the effect of CORT alone. Furthermore, T3 treatment overcame the iopanoic acid-induced reduction in the T4-CORT effect. Our findings indicate that thyroid hormones act synergistically with CORT to further augment the abundance of somatotrophs in vitro and that conversion of T4 to T3 within the pituitary is involved in T4 modulation of somatotroph abundance. Somatotroph differentiation during normal development may be regulated by complex interactions of hormones produced by the embryonic thyroid and adrenal glands.
Novel Neuropeptides Related to Frog Growth Hormone-Releasing Peptide: Isolation, Sequence, and Functional Analysis
Authors: Ukena Kazuyoshi , Koda Aya , Yamamoto Kazutoshi , Kobayashi Tetsuya , Iwakoshi-Ukena Eiko , Minakata Hiroyuki , Kikuyama Sakae , Tsutsui Kazuyoshi 
Published: June 2003

Abstract
We previously identified in the bullfrog a novel hypothalamic RFamide peptide (SLKPAANLPLRF-NH2) that stimulated GH release in vitro and in vivo and therefore was designated frog GH-releasing peptide (fGRP). Molecular cloning of cDNA encoding the deduced fGRP precursor polypeptide further revealed that it encodes fGRP and its related peptides (fGRP-RP-1, -RP-2, and -RP-3). In this study immunoaffinity purification using the antibody against fGRP was therefore conducted to determine whether these three putative fGRP-RPs exist as mature endogenous ligands in the frog brain. The mass peaks of the isolated immunoreactive substances were detected at 535.78, 1034.14, and 1079.71 m/z ([M+2H]2+), and their sequences, SIPNLPQRF-NH2, YLSGKTKVQSMANLPQRF-NH2, and AQYTNHFVHSLDTLPLRF-NH2, were revealed by the fragmentation, showing mature forms encoded in the cDNA sequences of fGRP-RP-1, -RP-2, and -RP-3, respectively. All of these fGRP-RPs contained a C-terminal -LPXRF-NH2 (X = L or Q) sequence, such as fGRP. This study further analyzed hypophysiotropic activities of the identified endogenous fGRP-RPs. Only fGRP-RP-2 stimulated, in a dose-related way, the release of PRL from cultured frog pituitary cells; its threshold concentration ranged from less than 10−7m. A similar stimulatory action of fGRP-RP-2 on GH release was evident. It was ascertained that fGRP-RP-2 was also effective in elevating the circulating GH and PRL levels when administered systemically. In contrast, fGRP-RPs did not have any appreciable effect on the release of gonadotropins. Thus, fGRP-RP-2 may act as a novel hypothalamic factor on the frog pituitary to stimulate the release of GH and PRL.
Deletion, But Not Antagonism, of the Mouse Growth Hormone Receptor Results in Severely Decreased Body Weights, Insulin, and Insulin-Like Growth Factor I Levels and Increased Life Span
Authors: Coschigano Karen T. , Holland Amy N. , Riders Markus E. , List Edward O. , Flyvbjerg Allan , Kopchick John J. 
Published: June 2003

AbstractGH participates in growth, metabolism, and cellular differentiation. To study these roles, we previously generated two different dwarf mouse lines, one expressing a GH antagonist (GHA) and the other having a disrupted GH receptor and binding protein gene (GHR −/−). In this study we compared the two dwarf lines in the same genetic background (C57BL/6J). One of the most striking differences between the mouse lines was their weight gain profile after weaning. The weights of the GHA dwarfs gradually approached controls over time, but the weights of the GHR −/− dwarfs remained low throughout the analysis period. Additionally, fasting insulin and glucose levels were reduced in the GHR −/− mice but normal in the GHA mice. IGF-I and IGF binding protein 3 (IGFBP-3) levels were significantly reduced, but by different degrees, in both mouse lines, but IGFBP-1 and -4 levels were reduced and IGFBP-2 levels increased in GHR −/− mice but unaltered in GHA mice. Finally, life span was significantly extended for the GHR −/− mice but remained unchanged for GHA dwarfs. These results suggest that the degree of blockade of GH signaling can lead to dramatically different phenotypes.
The Value of the Low-Dose Dexamethasone Suppression Test in the Differential Diagnosis of Hyperandrogenism in Women
Authors: Kaltsas Gregory A. , Isidori Andrea M. , Kola Blerina P. , Skelly Rob H. , Chew Shern L. , Jenkins Paul J. , Monson John P. , Grossman Ashley B. , Besser G. Michael 
Published: June 2003

We studied 211 hyperandrogenic women with respect to clinical presentation, basal androgen levels, and the degree of cortisol and androgen suppression during a 48-h low-dose (2 mg) dexamethasone-suppression test (LDDST) to exclude ovarian and adrenal tumors. In 42 women with elevated testosterone levels, 21 of whom failed to suppress testosterone during the LDDST, the response of serum androgen levels during a 4-wk administration of 7.5 mg prednisolone in a reverse circadian regimen was also assessed. These results were compared with an additional 17 patients with histologically proven androgen-secreting tumors.
Clinical presentation alone was suggestive of a virilizing tumor in 70% of patients with tumors. Serum testosterone, although occasionally only marginally elevated, was the sole androgen that was elevated in every patient with a tumor. After the LDDST, none of the patients with tumors obtained either a greater than 40% reduction or normalization of the previously elevated testosterone levels, whereas 88% of patients with nontumorous hyperandrogenism showed either normalization or suppression of more than 40%. With one exception, all of the patients with nontumorous hyperandrogenism who showed inadequate suppression of testosterone during the LDDST, and were treated with prednisolone, normalized the previously elevated androgens after 1 month of administration.
In summary, in women presenting with hyperandrogenism, lack of testosterone suppression during the LDDST is associated with 100% sensitivity and 88% specificity in distinguishing patients with ovarian and adrenal androgen-secreting tumors from patients with nontumorous hyperandrogenism in this small series. The LDDST is an easy to perform screening test that can also identify causes of hyperandrogenism due to altered glucocorticoid secretion.
Acute Temporal Regulation of Vascular Endothelial Growth/Permeability Factor Expression and Endothelial Morphology in the Baboon Endometrium by Ovarian Steroids
Authors: Albrecht Eugene D. , Aberdeen Graham W. , Niklaus Andrea L. , Babischkin Jeffery S. , Suresch Donna L. , Pepe Gerald J. 
Published: June 2003

We recently showed that endometrial vascular endothelial growth/permeability factor (VEG/PF) mRNA expression was decreased by ovariectomy of baboons and restored by chronic administration of estrogen. However, it remains to be determined whether this effect of estrogen reflects genomic up-regulation of VEG/PF and leads to an increase in microvascular permeability, an early physiological event in angiogenesis. Therefore, we determined the temporal expression of VEG/PF mRNA in glandular epithelial and stromal cells isolated by laser capture microdissection from and width of microvascular paracellular clefts that regulate vessel permeability in the endometrium of ovariectomized baboons after acute estradiol and/or progesterone administration.Endometrial VEG/PF mRNA levels were increased in five of five animals within 2 h of estradiol administration and remained elevated at 4 and 6 h. The net increase in glandular epithelial (7.31 ± 2.72 attomol/fmol 18S ribosomal rRNA) and stromal (3.13 ± 0.36) cell VEG/PF mRNA levels after estradiol administration was over 8-fold (P &lt; 0.05) and 2.6-fold (P &lt; 0.01) greater, respectively, than after vehicle (0.90 ± 0.30, glands and 1.20 ± 0.33, stroma). In contrast, endometrial VEG/PF mRNA expression was unaltered by progesterone. After estradiol treatment, endometrial paracellular cleft width was increased (P &lt; 0.01) from a mean (±se) of 71.6 ± 4.6 nm at 0 h to 101.1 ± 6.4 nm at 6 h, whereas vehicle or progesterone had no effect. We suggest that estrogen has a major role in regulating VEG/PF synthesis and early events in angiogenesis in the primate endometrium.
Novel Interactions of Adiponectin with the Endocrine System and Inflammatory Parameters
Authors: Fernández-Real José Manuel , López-Bermejo Abel , Casamitjana Roser , Ricart Wifredo 
Published: June 2003

Several markers of chronic immune activation have been found in association with obesity and insulin resistance. We aimed to study the interaction of adiponectin with chronic inflammation and known components of the insulin resistance syndrome.
Insulin sensitivity (minimal model analysis) and plasma soluble fractions of TNF-α receptor 1 (sTNFR1) and 2 (sTNFR2), adrenal and thyroid function, and adiponectin were evaluated in 68 apparently healthy subjects. An additional group of type 2 diabetic patients (n = 19) similarly studied, except for insulin sensitivity, were also included in the analysis.
As reported by others, serum adiponectin concentrations were higher in women than in men (13.55 ± 9.79 vs. 8.64 ± 7.83 mg/liter; P = 0.018). They were also higher in healthy subjects compared with diabetic patients (10.35 ± 8.48 vs. 7.41 ± 8.31 mg/liter; P = 0.021). As expected also, circulating adiponectin was significantly associated with waist to hip ratio (r = −0.28; P = 0.013), diastolic blood pressure (r = −0.25; P = 0.027), fasting plasma high-density lipoprotein cholesterol (r = 0.35; P = 0.001), triglycerides (r = −0.37; P = 0.001), and insulin sensitivity (r = 0.30; P = 0.011). Additionally, subjects in the higher quartile of circulating adiponectin had lower sTNFR2 concentrations (3.05 vs. 4.37 μg/liter; P = 0.012), a trend to lower sTNFR1 concentrations (1.76 vs. 2.20 μg/liter; P = 0.055), higher concentration of serum morning cortisol (16.86 vs. 13.52 μg/dl; P = 0.027), and higher serum free T4 levels (1.31 vs. 1.20 ng/dl; P = 0.038). Multiple regression analysis models were constructed to predict adiponectin concentrations. Predictive variables in these models included insulin sensitivity, waist to hip ratio and free T4, contributing to 17%, 10%, and 8% of adiponectin variance, respectively, These findings suggest that circulating adiponectin differentially modulates insulin action and that thyroid-axis, inflammatory cytokines, and the adrenal cortex might intervene in this modulation.
Endocrine and Metabolic Responses to Long-Term Monotherapy with the Antiepileptic Drug Valproate in the Normally Cycling Rhesus Monkey
Authors: Ferin Michel , Morrell Martha , Xiao Ennian , Kochan Lisa , Qian Fang , Wright Thomas , Sauer Mark 
Published: June 2003

An association between epilepsy and reproductive disturbances with an apparent increase in a polycystic ovarian syndrome (PCOS) has been reported. Whether this association can be attributed to epilepsy itself or is related to antiepileptic drug therapy, in particular valproate (VPA), remains controversial. We studied effects of a long-term VPA treatment on cycling monkeys, postulating that, if VPA monotherapy were to promote abnormal endocrine and metabolic parameters that are characteristic of PCOS, changes in cyclicity would be readily demonstrated.
After a 2-month control, a 12- to 15-month VPA monotherapy was initiated in 7 regularly cycling rhesus monkeys. Overall mean levels of VPA were 88.7 ± 4.0 (se) μg/ml. Mean body weight increased progressively during VPA treatment from 8.5 ± 0.5 kg before treatment to 9.6 ± 0.7 kg in the last week of treatment (P &lt; 0.05). Monkeys continued to have regular ovulatory menstrual cycles throughout VPA monotherapy. Length of the cycles was 28 ± 0.58 d in control and 28.4 ± 1.18 d in the last 3 months of VPA treatment. Follicular and luteal lengths and peak preovulatory estradiol and integrated luteal progesterone levels did not differ between control and treatment. Ovaries from VPA-treated monkeys showed histological evidence of ovulation, and none had characteristic features of PCOS. Endocrine PCOS markers, such as increased early follicular LH/FSH ratio and androgen levels were not different in control and VPA treatment cycles. LH and 17-hydroxyprogesterone responses to GnRH agonist challenges and the insulin response to glucose tolerance tests were similar in control and VPA groups. Lipid profiles were not affected by VPA treatment. The data indicate that a 12- to 15-month therapeutic exposure to VPA does not induce cyclic hormonal or morphological ovarian abnormalities or characteristics of the PCOS when administered to nonepileptic normally cycling nonhuman primates.
Microarray Analysis of Uterine Gene Expression in Mouse and Human Pregnancy
Authors: Bethin Kathleen E. , Nagai Yoshihiko , Sladek Robert , Asada Minoru , Sadovsky Yoel , Hudson Thomas J. , Muglia Louis J. 
Published: June 2003

AbstractImproved care of infants born prematurely has increased their survival. However, the incidence of preterm labor has not changed. To understand the processes involved in preterm labor, we used oligonucleotide microarrays to study gene expression in murine and human uterus during pregnancy. The induction of enzymes for prostaglandin synthesis was used as a marker for important changes during pregnancy because prostaglandins strongly contribute to both human and murine labor. We identified 504 genes that changed at least 2-fold between d 13.5 and 19.0 in the gravid mouse uterus. In the pregnant human myometrium, we found 478 genes that changed at least 2-fold in either term or preterm labor compared with preterm nonlabor specimens and 77 genes that significantly varied in both preterm and term labor. Patterns of gene regulation within functional groups comparing human preterm and term labor were similar, although the magnitude of change often varied. Surprisingly, few genes that changed significantly throughout pregnancy were the same in the mouse and human. These data suggest that functional progesterone withdrawal in human myometrium may not be the primary mechanism for labor induction, may implicate similar mechanisms for idiopathic preterm and term labor in humans, and may identify novel targets for further study.
Suppression of macho-1-directed muscle fate by FGF and BMP is required for formation of posterior endoderm in ascidian embryos
Authors: Kondoh Keisuke , Kobayashi Kenji , Nishida Hiroki 
Published: June 2003

Specification of germ layers is a crucial event in early embryogenesis. In embryos of the ascidian, Halocynthia roretzi, endoderm cells originate from two distinct lineages in the vegetal hemisphere. Cell dissociation experiments suggest that cell interactions are required for posterior endoderm formation, which has hitherto been thought to be solely regulated by localized egg cytoplasmic factors. Without cell interaction,every descendant of posterior-vegetal blastomeres, including endoderm precursors, assumed muscle fate. Cell interactions are required for suppression of muscle fate and thereby promote endoderm differentiation in the posterior endoderm precursors. The cell interactions take place at the 16- to 32-cell stage. Inhibition of cell signaling by FGF receptor and MEK inhibitor also supported the requirement of cell interactions. Consistently, FGF was a potent signaling molecule, whose signaling is transduced by MEK-MAPK. By contrast, such cell interactions are not required for formation of the anterior endoderm. Our results suggest that another redundant signaling molecule is also involved in the posterior endoderm formation, which is likely to be mediated by BMP.Suppression of the function of macho-1, a muscle determinant in ascidian eggs, by antisense oligonucleotide was enough to allow autonomous endoderm specification. Therefore, the cell interactions induce endoderm formation by suppressing the function of macho-1, which is to promote muscle fate. These findings suggest the presence of novel mechanisms that suppress functions of inappropriately distributed maternal determinants via cell interactions after embryogenesis starts. Such cell interactions would restrict the regions where maternal determinants work, and play a key role in marking precise boundaries between precursor cells of different tissue types.
Direct and concentration-dependent regulation of the proneural geneNeurogenin2by Pax6
Authors: Scardigli Raffaella , Bäumer Nicole , Gruss Peter , Guillemot François , Le Roux Isabelle 
Published: June 2003

Expression of the proneural gene Neurogenin2 is controlled by several enhancer elements, with the E1 element active in restricted progenitor domains in the embryonic spinal cord and telencephalon that express the homeodomain protein Pax6. We show that Pax6 function is both required and sufficient to activate this enhancer, and we identify one evolutionary conserved sequence in the E1 element with high similarity to a consensus Pax6 binding site. This conserved sequence binds Pax6 protein with low affinity both in vitro and in vivo, and its disruption results in a severe decrease in E1 activity in the spinal cord and in its abolition in the cerebral cortex. The regulation of Neurogenin2 by Pax6 is thus direct.Pax6 is expressed in concentration gradients in both spinal cord and telencephalon. We demonstrate that the E1 element is only activated by high concentrations of Pax6 protein, and that this requirement explains the restriction of E1 enhancer activity to domains of high Pax6 expression levels in the medioventral spinal cord and lateral cortex. By modifying the E1 enhancer sequence, we also show that the spatial pattern of enhancer activity is determined by the affinity of its binding site for Pax6. Together, these data demonstrate that direct transcriptional regulation accounts for the coordination between mechanisms of patterning and neurogenesis. They also provide evidence that Pax6 expression gradients are involved in establishing borders of gene expression domains in different regions of the nervous system.
Myf5 expression in somites and limb buds of mouse embryos is controlled by two distinct distal enhancer activities
Authors: Buchberger Astrid , Nomokonova Natalia , Arnold Hans-Henning 
Published: June 2003

The initiation of skeletal muscle development in the mouse embryo is strictly associated with the expression of the muscle-specific transcription factor Myf5, the first of four myogenic regulatory factors (MRFs) to be expressed in muscle progenitors, and ablation of the Myf5 gene prevents myogenesis. The complex spatiotemporal expression pattern of Myf5 depends on many discrete regulatory elements that are dispersed over long distances throughout the gene locus. These multiple control modules act differently in the various muscle precursor populations, presumably in response to diverse signals that control myogenesis. A potent enhancer region regulating Myf5 expression in limb muscles and somites has been identified previously at –58/–48 kb upstream of the transcriptional start site (Hadchouel et al., 2000). Here, we focus on the physical and functional dissection of this control region. We demonstrate that a conserved sequence of 270 bp located around –57 kb is required and sufficient to drive Myf5 expression in limbs and to maintain it in somites. A second enhancer nearby is responsible for Myf5 transcription in occipital/cranial somites. This enhancer activity also directs expression accurately to the myotome, preventing ectopic expression in the dermomyotome during the second phase of Myf5 gene activation in somites.Our data suggest that the enhancer identified here collaborates with other somitic enhancers to ensure correct myotomal Myf5 expression. Moreover, it constitutes an important element that mediates somitic expression after the initial and transient Myf5 activation through a previously described sonic hedgehog-dependent early epaxial enhancer.