A nodule describes an aggregation of similar cells or particles in a number of scientific fields:

• In medicine, a nodule refers to a small aggregation of cells.

• In geology, a nodule refers to a small knobbly rock or mineral cluster. (For example, Manganese nodule)

More on [ Nodule ]

PubMed: 0013-7227

{beta}-Adrenergic Receptor Mediated Protection Against Doxorubicin-Induced Apoptosis in Cardiomyocytes: the Impact of High Ambient Glucose.
Yano N, Suzuki D, Endoh M, Tseng A, Stabila JP, McGonnigal BG, Zhao TC, Padbury JF, Tseng YT Related Articles {beta}-Adrenergic Receptor Mediated Protection Against Doxorubicin-Induced Apoptosis in Cardiomyocytes: the Impact of High Ambient Glucose. Endocrinology. 2008 Aug 21; Authors: Yano N, Suzuki D, Endoh M, Tseng A, Stabila JP, McGonnigal BG, Zhao TC, Padbury JF, Tseng YT Recent studies have demonstrated that the beta2-adrenergic receptor (beta2AR)-Galphai signaling pathway exerts a cardiac anti-apoptotic effect. The goals of this study were to determine the intracellular signaling factors involved in beta2AR-mediated protection against doxorubicin-induced apoptosis in H9c2 cardiomyocyte and to explore the impact of high ambient glucose on the anti-apoptotic effect. Under physiological glucose environment (100mg/dL), beta2AR stimulation prevented doxorubicin-induced apoptosis which was attenuated by co-treatment with wortmannin, a PI3K inhibitor, or by transfection of a dominant negative Akt. Inhibition of Src kinase with PP2 or cSrc siRNA also attenuated the anti-apoptotic effect. Inhibition of PDGFR with AG1296 reversed the beta2AR-induced anti-apoptotic effect. Transfection of an active Src cDNA (Y529F) alone was sufficient to render the cells resistant to apoptosis and the resistance was blocked by wortmannin. Transfection of an active PI3K minigene (iSH2-p110) alone also induced resistance to apoptosis and the resistance was reversed by an Akt-inhibitor but not by AG1296. High ambient glucose (450mg/dL) caused two major effects: 1) it significantly reduced betaAR-induced PDGFR phosphorylation, Src kinase activity and activation of PI3K signaling pathway; 2) it partially attenuated beta2AR-induced anti-apoptotic effect. These data provide in vitro evidence supporting a signaling cascade by which beta2AR exerts a protective effect against doxorubicin-induced apoptosis via sequential involvement of Galphai, Gbetagamma, Src, PDGFR, PI3K and Akt. High ambient glucose significantly attenuates beta2AR-mediated cardioprotection by suppressing factors involved in this cascade including PDGFR, Src and PI3K/Akt. PMID: 18719028 [PubMed - as supplied by publisher]
UROCORTIN 1 INHIBITS RAT LEYDIG CELL FUNCTION.
Rivier CL Related Articles UROCORTIN 1 INHIBITS RAT LEYDIG CELL FUNCTION. Endocrinology. 2008 Aug 21; Authors: Rivier CL Corticotropin-releasing factor (CRF) has previously been reported in rat testes where it inhibits Leydig cells activity. However, recent studies in our laboratory have suggested that some of the effects originally attributed to CRF were instead due to the related peptide Urocortin 1 (Ucn 1) and that this latter hormone, not CRF, was detectable in Leydig cells. We show here that Ucn 1 [a mixed CRF receptors type 1 (CRFR1) and CRFR2 agonist] and the CRFR1-selective peptide stressin 1, but not Ucn 2 or Ucn 3 (both considered selective CRFR2 ligands), significantly blunt the testosterone (T) response to human chorionic gonadotropin (hCG). The effect of Ucn 1 is observed regardless of whether this peptide is injected intravenously or directly into the testes, and it is reversed by the mixed CRFR1/R2 antagonist Astressin B. Blockade of gonadotropin-releasing hormone receptors with the antagonist Azalin B does not interfere with the influence of Ucn 1, thereby demonstrating that pituitary luteinizing hormone does not appear to be involved in this model. Collectively, these results suggest that Ucn 1, not CRF, is present in the rat testes and interferes with Leydig cells activity. However, while we previously reported that alcohol upregulated gonadal Ucn 1 gene expression, CRF receptor antagonists were unable to reverse the inhibitory effect exerted by alcohol on hCG-induced T release. The functional role played by testicular Ucn 1 in stress models characterized by blunted androgen levels, therefore needs to be further investigated. PMID: 18719027 [PubMed - as supplied by publisher]
Nuclear factor {kappa}B (NF{kappa}B) mediates the inhibitory effects of tumor necrosis factor-alpha (TNF) on growth hormone (GH)-inducible gene expression in liver.
Buzzelli MD, Nagarajan M, Radtka JF, Shumate ML, Navaratnarajah M, Lang CH, Cooney RN Related Articles Nuclear factor {kappa}B (NF{kappa}B) mediates the inhibitory effects of tumor necrosis factor-alpha (TNF) on growth hormone (GH)-inducible gene expression in liver. Endocrinology. 2008 Aug 21; Authors: Buzzelli MD, Nagarajan M, Radtka JF, Shumate ML, Navaratnarajah M, Lang CH, Cooney RN TNF inhibits serine protease inhibitor 2.1 (Spi 2.1) and insulin-like growth factor-I (IGF-I) gene expression by GH in CWSV-1 hepatocytes. The current study describes construction of a GH-inducible IGF-I promoter construct and investigates mechanisms by which TNF and NFkappaB inhibit GH-inducible gene expression. CWSV-1 cells were transfected with GH-inducible Spi 2.1 or IGF-I promoter luciferase constructs, incubated with TNF signaling inhibitors (fumonisin B1 for sphingomyelinase and SP600125 for JNK), treated +/- TNF, then stimulated with rhGH. The 5-6 fold induction of Spi 2.1 and IGF-I promoter activity by GH was inhibited by TNF. Neither fumonisin B1 nor SP600125 prevented the inhibitory effects of TNF on GH-inducible promoter activity. Dominant negative inhibitor kappa-B alpha (IkappaBalpha) expression vectors (IkappaBalphaS/A or IkappaBalphaTrunc), p65 and p50 expression vectors, and p65 deletion constructs were used to investigate the NFkappaB pathway. IkappaBalphaS/A and IkappaBalphaTrunc ameliorated the inhibitory effects of TNF on GH-inducible Spi 2.1 and IGF-I promoter activity. Co-transfection of CWSV-1 cells with expression vectors for p65 alone or p50 and p65 together inhibited GH-inducible Spi 2.1 and IGF-I promoter activity. Co-transfection with a C-terminus p65 deletion (1-450) enhanced GH-inducible promoter activity, while the N-terminal deletion (31-551) was inhibitory for IGF-I, but not Spi 2.1. Cycloheximide did not antagonize the inhibitory effects of TNF on GH-inducible IGF-I expression. We conclude the inhibitory effects of TNF on GH-inducible promoter activity are mediated by NFkappaB, especially p65, by a mechanism that does not require protein synthesis. PMID: 18719026 [PubMed - as supplied by publisher]
Estrogen actions in the male reproductive system involve ERE-independent pathways.
Weiss J, Bernhardt ML, Laronda MM, Hurley LA, Glidewell-Kenney C, Pillai S, Tong M, Korach KS, Jameson JL Related Articles Estrogen actions in the male reproductive system involve ERE-independent pathways. Endocrinology. 2008 Aug 21; Authors: Weiss J, Bernhardt ML, Laronda MM, Hurley LA, Glidewell-Kenney C, Pillai S, Tong M, Korach KS, Jameson JL The estrogen receptor alpha (ERalpha) acts through multiple pathways, including estrogen response element (ERE)-dependent ("classical") and ERE-independent ("non-classical") mechanisms. We previously created a mouse model harboring a two amino acid mutation of the DNA-binding domain (E207A, G208A) that precludes direct binding of ERalpha to an ERE. After crossing heterozygous mutant mice with an ERalpha knockout line, it was possible to assess the degree of physiologic rescue by the isolated ERalpha non-classical allele (-/AA; "AA") when compared to ERKO mice (-/-; "ERKO") and to wildtypess (+/+; "WT"). In male ERKO mice up to 8 months of age, testosterone levels were high, though LH levels were similar to WT. Testosterone was normal in the AA mice, indicating that the AA allele rescues the enhanced testosterone biosynthesis in ERKO mice. Male ERKO mice exhibited distention of the seminiferous tubules as early as 2-3 months of age as a consequence of decreased water resorption in the efferent ducts. By 3-4 months of age, ERKO mice had impaired spermatogenesis in approximately 40% of their tubules, and sperm counts and motility declined in association with the histologic changes. In the AA mice, histologic defects were greatly reduced or absent and sperm counts and motility were rescued. Levels of Aquaporins 1 and 9, which contribute to water uptake in the efferent ducts, were reduced in ERKO mice and partially or fully rescued in AA mice, whereas another water transporter, NHE3, was decreased in both ERKO and AA mice. We conclude that non-ERE dependent estrogen pathways are sufficient to rescue the defective spermatogenesis observed in ERKO mice and play a prominent role in ERalpha action in the testis, including pathways that regulate water resorption and androgen biosynthesis. PMID: 18719025 [PubMed - as supplied by publisher]
Expression of the transcriptional repressor ATF3 in gonadotrophs is regulated by Egr-1, CREB and ATF2 following GnRH receptor stimulation.
Mayer SI, Dexheimer V, Nishida E, Kitajima S, Thiel G Related Articles Expression of the transcriptional repressor ATF3 in gonadotrophs is regulated by Egr-1, CREB and ATF2 following GnRH receptor stimulation. Endocrinology. 2008 Aug 21; Authors: Mayer SI, Dexheimer V, Nishida E, Kitajima S, Thiel G Stimulation of gonadotropin-releasing hormone (GnRH) receptors enhances expression of activating transcription factor (ATF) 3 in a pituitary gonadotroph cell line. The signaling pathway requires elevated cytosolic Ca(2+) levels, and activation of extracellular signal-regulated protein kinase and c-Jun N-terminal protein kinase. The signaling cascade was blocked by overexpression of either MAP kinase phosphatase (MKP)-1 or MAP kinase phosphatase-5 that dephosphorylate nuclear ERK and JNK. In addition, ATF3 biosynthesis was impaired following lentiviral-mediated expression of a constitutively active mutant of calcineurin A. Thus, MKP-1, MKP-5 and calcineurin may function as shut-off devices for GnRH receptor signaling. Expression of dominant-negative mutants of Egr-1, CREB and ATF2 blocked the biosynthesis of ATF3, indicating that these transcription factors connect the intracellular signaling cascade elicited by activation of GnRH receptors with transcription of the ATF3 gene. This view was corroborated by chromatin immunoprecipitation experiments revealing that Egr-1 and the phosphorylated forms of CREB and ATF2 bound to the 5'-upstream region of the ATF3 gene in buserelin-stimulated gonadotrophs. Together, the data indicate that the ATF3 gene is a bona fide target gene of Egr-1, CREB and ATF2 in gonadotrophs. Moreover, we show that in gonadotrophs ATF3 bound to its own promoter under physiological conditions. The analysis of lentiviral-transmitted ATF3 promoter/luciferase reporter genes, embedded into the chromatin of the cells, revealed that ATF3 blocked the activity of its own promoter. We additionally identified the chromogranin B gene as bona fide target gene of ATF3 in gonadotrophs. PMID: 18719024 [PubMed - as supplied by publisher]
Epigallocatechin gallate (EGCG) stabilizes p27kip1 in estrogen- stimulated MCF-7 cells through downregulation of the Skp2 protein.
Huang HC, Way TD, Lin CL, Lin JK Related Articles Epigallocatechin gallate (EGCG) stabilizes p27kip1 in estrogen- stimulated MCF-7 cells through downregulation of the Skp2 protein. Endocrinology. 2008 Aug 21; Authors: Huang HC, Way TD, Lin CL, Lin JK Loss of p27 (Kip1) is associated with a poor prognosis in breast cancer. According to previous findings, a decrease in p27 (Kip1) levels is mainly the result of enhanced proteasome-dependent degradation mediated by its specific ubiquitin ligase subunit Skp2. Epigallocatechin gallate (EGCG), the main constituent of green tea, was found to stabilize p27 (Kip1) levels in breast cancer, but whether this effect is mediated through changes in Skp2 expression remains unclear. Here, we investigated the mechanisms involved in EGCG's growth inhibition of estrogen-responsive human breast cancer MCF-7 cells. In our results, EGCG increased p27(Kip1) and decreased Skp2 in a time- and dose-dependent manner, suggesting that p27(Kip1) and Skp2 may be involved in the growth inhibition by EGCG in estrogen-stimulated MCF-7 cells. Interestingly, mRNA levels of p27 (Kip1) and Skp2 did not significant change in estrogen-stimulated MCF-7 cells following EGCG treatments. Moreover, overexpression of Skp2 in MCF-7 cells prevented accumulation of p27 (Kip1) and promoted resistance to the antiproliferative effects of EGCG. This suggests that the downregulation of the F-box protein Skp2 is the mechanism underlying p27 (Kip1) accumulation. Furthermore, both tamoxifen and paclitaxel significantly and synergistically enhanced the growth inhibition of MCF-7 cells by EGCG through the downregulation of Skp2 protein. However, the downregulation of Skp2 was not always correlate with the upregulation of p27, suggesting that EGCG dependent Skp2 downregulation can influence on cell growth in several ways. The therapeutic strategies designed to reduce Skp2 may therefore play an important clinical role in treatment of breast cancer cells. PMID: 18719023 [PubMed - as supplied by publisher]

PubMed: 0804-4643

Elevated free IGF-II levels in localized, early-stage breast cancer in women.
Espelund U, Cold S, Frystyk J, Orskov H, Flyvbjerg A Related Articles Elevated free IGF-II levels in localized, early-stage breast cancer in women. Eur J Endocrinol. 2008 Aug 21; Authors: Espelund U, Cold S, Frystyk J, Orskov H, Flyvbjerg A Objective. Epidemiological studies imply an association between circulating insulin-like growth factor I (IGF-I) and breast cancer, whereas the role of IGF-II, which also acts on the IGF-I receptor, is less settled. This study investigates the association between IGF-II and breast cancer in patients with localized disease. Design. The participants were women with well-characterized, early stage, localized breast cancer (n=43) and matched healthy women (n=38), from whom fasting serum levels of IGF-related peptides were measured. Results. In patients, mean free IGF-II was increased (+57%, P<0.001) in spite of reduced total IGF-II levels (-12%, P=0.003) as compared to controls. Similar changes were seen in free IGF-I (+28%, P=0.004) and total IGF-I (-16% P=NS). Pro-IGF-II and IGF binding protein 1 (IGFBP-1) were unchanged. IGFBP-2 was reduced by 22% in the patients (P=0.004). Patients showed reduced IGFBP-3 protease activity and accordingly increased levels of intact IGFBP-3, whereas total IGFBP-3 was unchanged. Conclusion. Women with localized, early-stage breast cancer show elevated circulating free IGF-I and -II, reduced total IGF-II and alterations in IGFBPs. The changes observed despite minimal cancer disease suggest a role for the circulating IGF-system in the progression of breast cancer in women. PMID: 18719053 [PubMed - as supplied by publisher]
Sleep and the epidemic of obesity in children and adults.
Van Cauter E, Knutson K Related Articles Sleep and the epidemic of obesity in children and adults. Eur J Endocrinol. 2008 Aug 21; Authors: Van Cauter E, Knutson K Sleep is an important modulator of neuroendocrine function and glucose metabolism in children as well as in adults. In recent years, sleep curtailment has become a hallmark of modern society with both children and adults having shorter bedtimes than a few decades ago. This trend for shorter sleep duration has developed over the same time period as the dramatic increase in the prevalence of obesity. There is rapidly accumulating evidence from both laboratory studies and epidemiologic studies to indicate that chronic partial sleep loss may increase the risk of obesity and weight gain. The present article reviews laboratory evidence indicating that sleep curtailment in young adults results in a constellation of metabolic and endocrine alterations, including decreased glucose tolerance, decreased insulin sensitivity, elevated sympatho-vagal balance, increased evening concentrations of cortisol, increased levels of ghrelin levels, decreased levels of leptin and increased hunger and appetite. We also review cross-sectional epidemiologic studies associating short sleep with increased body mass index and prospective epidemiologic studies that have shown an increased risk of weight gain and obesity in children and young adults who are short sleepers. Altogether, the evidence points to a possible role of decreased sleep duration in the current epidemic of obesity. PMID: 18719052 [PubMed - as supplied by publisher]

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