bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Role for Notch Signaling in Stromal Survival and Differentiation during Prostate Development
Authors: Orr Brigid , Grace O. Cathal , Vanpoucke Griet , Ashley George R. , Thomson Axel A. 
Published: September 2008

Notch1 signaling is involved in epithelial growth and differentiation of prostate epithelia, and we have examined the role that notch signaling plays in the stroma of the developing prostate. We initially observed expression of δ-like 1 (Dlk1) and Notch2 in gene profiling studies of prostatic mesenchyme, and anticipated that they might be expressed in a key subset of inductive mesenchyme. Using quantitative RT-PCR, Northern blotting, and whole mount in situ hybridization, we confirmed that both Dlk1 and Notch2 mRNAs showed a restricted expression pattern within subsets of the stroma during prostate development. Localization of Dlk1 and Notch2 proteins mirrored the transcript expression, and showed both distinct and overlapping expression patterns within the stroma. Dlk1 and Notch2 were coexpressed in condensed inductive mesenchyme of the ventral mesenchymal pad (VMP), and were partially colocalized in the smooth muscle (SM) layer of the urethral stroma. In addition, Dlk1 was not expressed in SM adjacent to the VMP in female urethra. The function of notch signaling was examined using organ cultures of prostate rudiments and a small molecule inhibitor of notch receptor activity. Inhibition of notch signaling led to a loss of stromal tissue in both prostate and female VMP cultures, suggesting that this pathway was required for stromal survival. Inhibition of notch signaling also led to changes in both epithelial and stromal differentiation, which was evident in altered distributions of SM α-actin and p63 in prostates grown in vitro. The effects of notch signaling upon the stroma were only evident in the presence of testosterone, in contrast to effects upon epithelial differentiation.Studies on the expression of delta-like 1 homolog (Dlk1) and Notch 2 in prostatic mesenchyme shows that inhibition of notch signaling leads to defects in mesenchymal differentiation.
Central Leptin Regulates Total Ceramide Content and Sterol Regulatory Element Binding Protein-1C Proteolytic Maturation in Rat White Adipose Tissue
Authors: Bonzón-Kulichenko Elena , Schwudke Dominik , Gallardo Nilda , Moltó Eduardo , Fernández-Agulló Teresa , Shevchenko Andrej , Andrés Antonio 
Published: September 2008

Obesity and type 2 diabetes are associated with insulin and leptin resistance, and increased ceramide contents in target tissues. Because the adipose tissue has become a central focus in these diseases, and leptin-induced increases in insulin sensitivity may be related to effects of leptin on lipid metabolism, we investigated herein whether central leptin was able to regulate total ceramide levels and the expression of enzymes involved in ceramide metabolism in rat white adipose tissue (WAT). After 7 d central leptin treatment, the total content of ceramides was analyzed by quantitative shotgun lipidomics mass spectrometry. The effects of leptin on the expression of several enzymes of the sphingolipid metabolism, sterol regulatory element binding protein (SREBP)-1c, and insulin-induced gene 1 (INSIG-1) in this tissue were studied. Total ceramide levels were also determined after surgical WAT denervation. Central leptin infusion significantly decreased both total ceramide content and the long-chain fatty acid ceramide species in WAT. Concomitant with these results, leptin decreased the mRNA levels of enzymes involved in de novo ceramide synthesis (SPT-1, LASS2, LASS4) and ceramide production from sphingomyelin (SMPD-1/2). The mRNA levels of enzymes of ceramide degradation (Asah1/2) and utilization (sphingomyelin synthase, ceramide kinase, glycosyl-ceramide synthase, GM3 synthase) were also down-regulated. Ceramide-lowering effects of central leptin were prevented by local autonomic nervous system denervation of WAT. Finally, central leptin treatment markedly increased INSIG-1 mRNA expression and impaired SREBP-1c activation in epididymal WAT. These observations indicate that in vivo central leptin, acting through the autonomic nervous system, regulates total ceramide levels and SREBP-1c proteolytic maturation in WAT, probably contributing to improve the overall insulin sensitivity.Central leptin decreases total ceramide levels and prevents sterol regulatory element binding protein (SREBP-1C) proteolytic maturation in white adipose tissue, and probably, in this way, contributes to improve the overall insulin sensitivity.
Progestin Signaling through an Olfactory G Protein and Membrane Progestin Receptor-α in Atlantic Croaker Sperm: Potential Role in Induction of Sperm Hypermotility
Authors: Tubbs Christopher , Thomas Peter 
Published: September 2008

Progestin stimulation of sperm hypermotility remains poorly understood despite having been described in numerous vertebrate species. We show here that progestin stimulation of sperm hypermotility in a teleost, the Atlantic croaker (Micropogonias undulatus) is associated with activation of an olfactory G protein (Golf). Furthermore, we provide evidence that this progestin action is mediated by membrane progestin receptor-α (mPRα). Golf was identified in croaker sperm membranes and was specifically activated after treatment with the progestin 17,20β,21-trihydroxy-4-pregnen-3-one (20β-S). Treatment of sperm membranes with 20β-S caused an increase in cAMP production, which was blocked by pretreatment with cholera toxin and two membrane adenylyl cyclase inhibitors: 2′,5′-dideoxyadenosine and SQ22536. Moreover, preincubation of croaker sperm with 2′,5′-dideoxyadenosine and SQ22536 resulted in a significant inhibition of 20β-S-stimulated hypermotility. Binding of [3H]20β-S to sperm membranes was decreased after pretreatment with GTPγS but not pertussis toxin, suggesting the receptor is coupled to a pertussis toxin-insensitive G protein. Golf and mPRα were coexpressed on the sperm midpiece and flagella and were coimmunoprecipitated from sperm membranes. Finally, expression of mPRα protein on sperm increased after in vivo treatment with LHRH and was associated with increased induction of sperm motility by 20β-S. These results suggest that 20β-S activates mPRα in croaker sperm, which in turn activates Golf and membrane adenylyl cyclase to stimulate sperm hypermotility. Taken together these findings provide a plausible mechanism by which progestins stimulate sperm hypermotility in croaker and provide the first evidence of hormonal activation of Golf in any species.Progestin activation of an olfactory G protein pathway, likely through membrane progestin receptor alpha, is associated with induction of hypermotility in Atlantic croaker sperm.
Cortisol Reduces Gonadotropin-Releasing Hormone Pulse Frequency in Follicular Phase Ewes: Influence of Ovarian Steroids
Authors: Oakley Amy E. , Breen Kellie M. , Clarke Iain J. , Karsch Fred J. , Wagenmaker Elizabeth R. , Tilbrook Alan J. 
Published: September 2008

Stress-like elevations in plasma glucocorticoids suppress gonadotropin secretion and can disrupt ovarian cyclicity. In sheep, cortisol acts at the pituitary to reduce responsiveness to GnRH but does not affect GnRH pulse frequency in the absence of ovarian hormones. However, in ewes during the follicular phase of the estrous cycle, cortisol reduces LH pulse frequency. To test the hypothesis that cortisol reduces GnRH pulse frequency in the presence of ovarian steroids, the effect of cortisol on GnRH secretion was monitored directly in pituitary portal blood of follicular phase sheep in the presence and absence of a cortisol treatment that elevated plasma cortisol to a level observed during stress. An acute (6 h) cortisol increase in the midfollicular phase did not lower GnRH pulse frequency. However, a more prolonged (27 h) increase in cortisol beginning just before the decrease in progesterone reduced GnRH pulse frequency by 45% and delayed the preovulatory LH surge by 10 h. To determine whether the gonadal steroid milieu of the follicular phase enables cortisol to reduce GnRH pulse frequency, GnRH was monitored in ovariectomized ewes treated with estradiol and progesterone to create an artificial follicular phase. A sustained increment in plasma cortisol reduced GnRH pulse frequency by 70% in this artificial follicular phase, in contrast to the lack of an effect in untreated ovariectomized ewes as seen previously. Thus, a sustained stress-like level of cortisol suppresses GnRH pulse frequency in follicular phase ewes, and this appears to be dependent upon the presence of ovarian steroids.A sustained stress-like level of cortisol reduces GnRH pulse frequency in the follicular phase and appears to require the presence of ovarian steroids.
Regenerative Potentials of the Murine Thyroid in Experimental Autoimmune Thyroiditis: Role of CD24
Authors: Chen Cindy Y. , Kimura Hiroaki , Landek-Salgado Melissa A. , Hagedorn Judith , Kimura Miho , Suzuki Koichi , Westra William , Rose Noel R. , Caturegli Patrizio 
Published: September 2008

Hashimoto thyroiditis can be partially reproduced in mice by immunization with thyroglobulin or, more recently, thyroperoxidase. This experimental autoimmune thyroiditis (EAT) model has been extensively characterized during early disease phases (up to d 35 after immunization). By extending the analysis of EAT to 100 d after immunization, we noted a remarkable regenerative capacity of the thyroid and the expression of Oct-4, suggesting in vivo the existence of adult thyroid stem cells. After an almost complete destruction of the follicular architecture, occurring between d 21 and 28, the thyroid was capable of restoring its follicles and reducing the mononuclear infiltration, so that by d 100 after immunization, it regained its normal morphology and function. During this regeneration process, thyrocytes expressed high levels of CD24. We therefore assessed the role of CD24 in thyroid regeneration by inducing EAT in mice lacking CD24. Regeneration was faster in the absence of CD24, likely a consequence of the effect of CD24 on the infiltrating lymphocytes. The study suggests that the EAT model can also be used as a tool to investigate adult thyroid stem cells.The murine thyroid is capable of restoring its architecture after an insult that almost completely destroys it.
Functional Characterization and Structural Modeling of Obesity Associated Mutations in the Melanocortin 4 Receptor
Authors: Tan Karen , Pogozheva Irina D. , Yeo Giles S. H. , Hadaschik Dirk , Keogh Julia M. , Haskell-Leuvano Carrie , O'Rahilly Stephen , Mosberg Henry I. , Farooqi I. Sadaf 
Published: September 2008

Mutations in the melanocortin 4 receptor (MC4R) gene are the most common known cause of monogenic human obesity. The MC4R gene was sequenced in 2000 subjects with severe early-onset obesity. We detected seven different nonsense and 19 nonsynonymous mutations in a total of 94 probands, some of which have been reported previously by others. We functionally characterized the 11 novel obesity associated missense mutations. Seven of these mutants (L54P, E61K, I69T, S136P, M161T, T162I, and I269N) showed impaired cell surface trafficking, reduced level of maximal binding of the radioligand [125I]NDP-MSH, and reduced ability to generate cAMP in response to ligand. Four mutant MC4Rs (G55V, G55D, S136F, and A303T) displayed cell surface expression and agonist binding similar to the wild-type receptor but showed impaired cAMP production, suggesting that these residues are likely to be critical for conformational rearrangement essential for receptor activation. Homology modeling of these mutants using a model of MC4R based on the crystal structure of the β2-adrenoreceptor was used to provide insights into the possible structural basis for receptor dysfunction. Transmembrane (TM) domains 1, 3, 6, 7, and peripheral helix 8 appear to participate in the agonist-induced conformational rearrangement necessary for coupling of ligand binding to signaling. We conclude that G55V, G55D, S136F, and A303T mutations are likely to strengthen helix-helix interactions between TM1 and TM2, TM3 and TM6, and TM7 and helix 8, respectively, preventing relative movement of these helices during receptor activation. The combination of functional studies and structural modeling of naturally occurring pathogenic mutations in MC4R can provide valuable information regarding the molecular mechanism of MC4R activation and its dysfunction in human disease.
Among obesity-associated melanocortin-4 receptor mutations, four transmembrane domains and peripheral helix 8 are necessary for coupling of ligand binding to signaling.
Mice Lacking β-Adrenergic Receptors Have Increased Bone Mass but Are Not Protected from Deleterious Skeletal Effects of Ovariectomy
Authors: Bouxsein M. L. , Devlin M. J. , Glatt V. , Dhillon H. , Pierroz D. D. , Ferrari S. L. 
Published: September 2008

Activation of β2-adrenergic receptors inhibits osteoblastic bone formation and enhances osteoclastic bone resorption. Whether β-blockers inhibit ovariectomy-induced bone loss and decrease fracture risk remains controversial. To further explore the role of β-adrenergic signaling in skeletal acquisition and response to estrogen deficiency, we evaluated mice lacking the three known β-adrenergic receptors (β-less). Body weight, percent fat, and bone mineral density were significantly higher in male β-less than wild-type (WT) mice, more so with increasing age. Consistent with their greater fat mass, serum leptin was significantly higher in β-less than WT mice. Mid-femoral cross-sectional area and cortical thickness were significantly higher in adult β-less than WT mice, as were femoral biomechanical properties (+28 to +49%, P &lt; 0.01). Young male β-less had higher vertebral (1.3-fold) and distal femoral (3.5-fold) trabecular bone volume than WT (P &lt; 0.001 for both) and lower osteoclast surface. With aging, these differences lessened, with histological evidence of increased osteoclast surface and decreased bone formation rate at the distal femur in β-less vs. WT mice. Serum tartrate-resistance alkaline phosphatase-5B was elevated in β-less compared with WT mice from 8–16 wk of age (P &lt; 0.01). Ovariectomy inhibited bone mass gain and decreased trabecular bone volume/total volume similarly in β-less and WT mice. Altogether, these data indicate that absence of β-adrenergic signaling results in obesity and increased cortical bone mass in males but does not prevent deleterious effects of estrogen deficiency on trabecular bone microarchitecture. Our findings also suggest direct positive effects of weight and/or leptin on bone turnover and cortical bone structure, independent of adrenergic signaling.
Mice lacking ß-adrenergic receptors have increased body weight, bone mineral density, and bone turnover versus controls, but are not protected from bone loss due to deficiency of estrogens..
A Crucial Role for Gαq/11, But Not Gαi/o or Gαs, in Gonadotropin-Releasing Hormone Receptor-Mediated Cell Growth Inhibition
Authors: White Colin D. , Coetsee Marla , Morgan Kevin , Flanagan Colleen A. , Millar Robert P. , Lu Zhi-Liang 
Published: September 2008

AbstractGnRH acts on its cognate receptor in pituitary gonadotropes to regulate the biosynthesis and secretion of gonadotropins. It may also have direct extrapituitary actions, including inhibition of cell growth in reproductive malignancies, in which GnRH activation of the MAPK cascades is thought to play a pivotal role. In extrapituitary tissues, GnRH receptor signaling has been postulated to involve coupling of the receptor to different G proteins. We examined the ability of the GnRH receptor to couple directly to Gαq/11, Gαi/o, and Gαs, their roles in the activation of the MAPK cascades, and the subsequent cellular effects. We show that in Gαq/11-negative cells stably expressing the GnRH receptor, GnRH did not induce activation of ERK, jun-N-terminal kinase, or P38 MAPK. In contrast to Gαi or chimeric Gαqi5, transfection of Gαq cDNA enabled GnRH to induce phosphorylation of ERK, jun-N-terminal kinase, and P38. Furthermore, no GnRH-mediated cAMP response or inhibition of isoproterenol-induced cAMP accumulation was observed. In another cellular background, [35S]GTPγS binding assays confirmed that the GnRH receptor was unable to directly couple to Gαi but could directly interact with Gαq/11. Interestingly, GnRH stimulated a marked reduction in cell growth only in cells expressing Gαq, and this inhibition could be significantly rescued by blocking ERK activation. We therefore provide direct evidence, in multiple cellular backgrounds, that coupling of the GnRH receptor to Gαq/11, but not to Gαi/o or Gαs, and consequent activation of ERK plays a crucial role in GnRH-mediated cell death.
Steroidal Androgens and Nonsteroidal, Tissue-Selective Androgen Receptor Modulator, S-22, Regulate Androgen Receptor Function through Distinct Genomic and Nongenomic Signaling Pathways
Authors: Narayanan Ramesh , Coss Christopher C. , Yepuru Muralimohan , Kearbey Jeffrey D. , Miller Duane D. , Dalton James T. 
Published: September 2008

AbstractAndrogen receptor (AR) ligands are important for the development and function of several tissues and organs. However, the poor oral bioavailability, pharmacokinetic properties, and receptor cross-reactivity of testosterone, coupled with side effects, place limits on its clinical use. Selective AR modulators (SARMs) elicit anabolic effects in muscle and bone, sparing reproductive organs like the prostate. However, molecular mechanisms underlying the tissue selectivity remain ambiguous. We performed a variety of in vitro studies to compare and define the molecular mechanisms of an aryl propionamide SARM, S-22, as compared with dihydrotestosterone (DHT). Studies indicated that S-22 increased levator ani muscle weight but decreased the size of prostate in rats. Analysis of the upstream intracellular signaling events indicated that S-22 and DHT mediated their actions through distinct pathways. Modulation of these pathways altered the recruitment of AR and its cofactors to the PSA enhancer in a ligand-dependent fashion. In addition, S-22 induced Xenopus laevis oocyte maturation and rapid phosphorylation of several kinases, through pathways distinct from steroids. These studies reveal novel differences in the molecular mechanisms by which S-22, a nonsteroidal SARM, and DHT mediate their pharmacological effects.
PECAM-1 is a critical mediator of atherosclerosis
Authors: Stevens Hazel Y. , Melchior Benoît , Bell Kelly S. , Yun Sujin , Yeh Jiunn-Chern , Frangos John A. 
Published: September 2008

SUMMARYAtherosclerosis is a chronic inflammatory disease of large arteries in which lesion development preferentially occurs at vessel sites exposed to rapid changes in flow. We have previously shown that platelet endothelial cell adhesion molecule (PECAM-1), a surface receptor of the immunoglobulin superfamily, is involved in mechanosensing of rapid changes in flow. We wondered whether apolipoprotein E deficient (ApoE−/−) mice, predisposed to development of atheromas, would be protected from atherosclerosis by deficiency in PECAM-1. Using double knockout (DKO) mice for both PECAM-1 and ApoE (ApoE−/−/PECAM-1−/−) we found a significant reduction of sudanophilic lesions in their aortae compared to single knockout (SKO) (ApoE−/−/PECAM-1+/+) mice maintained on a high-fat Western diet. Immunostaining of aortic sinus cross sections demonstrated significantly lower ICAM-1 expression in DKO lesions compared with SKO lesions, and en face preparations of vessel regions subjected to disturbed and laminar flow showed less disruption of junctional connexin 43 in DKO than in SKO mice. Thus, PECAM-1 deficiency reduced the extent of lesions at the aortic arch and the aortic sinus, and lowered atherogenic indices. These results suggest that PECAM-1 is an important factor in the atherogenic changes seen in the ApoE-deficient mouse model and thus should be considered as a potential target for protection against atherosclerosis.
An innate immune response of blood cells to tumors and tissue damage in Drosophila
Authors: Pastor-Pareja José Carlos , Wu Ming , Xu Tian 
Published: September 2008

SUMMARY
Studies in mice and humans have demonstrated a role for the immune system in preventing the growth of tumors. Deciphering the mechanisms involved in the immune response to tumors is essential to our understanding of immune recognition and cancer progression. Here we report an innate immune response to tumors in Drosophila melanogaster. We found that circulating blood cells, termed hemocytes, adhere to tumors upon detection of basement membrane disruption, and subsequently counter their growth. Basement membrane components are remarkably conserved throughout the animal kingdom, providing a unique structure for the immune system to sense tissue integrity. Further, we show that tissue damage activates JNK signaling in both tumors and aseptic wounds, causing expression of JAK/STAT-activating cytokines. Cytokine secretion from the injured tissue is amplified into a systemic response through the induction of additional cytokine expression in the hemocytes and the fat body, resulting in hemocyte proliferation. Our findings reveal common mechanisms in the response to tumors and wounds in flies. A similar innate reaction may underlie the response to tumors and tissue damage in vertebrates and humans.
Natural variation in plasticity of glucose homeostasis and food intake
Authors: Kaun Karla R. , Chakaborty-Chatterjee Munmun , Sokolowski Marla B. 
Published: September 2008

SUMMARY
Balancing the acquisition, allocation and storage of energy during periods of food deprivation is critical for survival. We show that natural variation in the foraging (for) gene, which encodes a cGMP-dependent protein kinase (PKG) in the fruit fly Drosophila melanogaster,affects behavioral and physiological responses to short-term food deprivation. Rover and sitter, natural allelic variants of for, differ in their stored carbohydrate reserves as well as their response to short-term deprivation. Fewer carbohydrates are stored in the fat body of rovers compared with sitters, and more labeled glucose is allocated to lipid stores compared with carbohydrate stores during a short feeding bout. Short-term food deprivation decreases hemolymph glucose levels in rovers but not in sitters. After food deprivation, rovers increase their food intake more slowly than sitters, and rover hemolymph levels take longer to respond to re-feeding. Finally, rovers have lower adipokinetic hormone (akh) mRNA levels than sitters. Our data suggest that for mediates larval responses to short-term food deprivation by altering food intake and blood glucose levels.
African penguins (Spheniscus demersus) can detect dimethyl sulphide, a prey-related odour
Authors: Cunningham Gregory B. , Strauss Venessa , Ryan Peter G. 
Published: September 2008

SUMMARY
Although it is well established that certain procellariiform seabirds use odour cues to find prey, it is not clear whether penguins use olfactory cues to forage. It is commonly assumed that penguins lack a sense of smell, yet they are closely related to procellariiforms and forage on similar types of prey in similar areas to many procellariiforms. Such regions are characterized by having high levels of dimethyl sulphide (DMS) a scented compound that many marine animals use to locate foraging grounds. If penguins can smell, DMS may be a biologically relevant scented compound that they may be sensitive to in nature. To test this hypothesis, we investigated whether adult African penguins (Spheniscus demersus) could detect DMS using two separate experiments. We tested wild penguins on Robben Island, South Africa, by deploying μmolar DMS solutions in the colonies, and found that birds slowed down their walking speeds. We also tested captive penguins in a Y-maze. In both cases, our data convincingly demonstrate that African penguins have a functioning sense of smell and are attracted to DMS. The implication of this work is that the detection of changes in the odour landscape (DMS) may assist penguins in identifying productive areas of the ocean for foraging. At-sea studies are needed to investigate this issue further.